TY - JOUR T1 - Variation in resting heart rate over 4 years and the risks of myocardial infarction and death among older adults. JF - Heart Y1 - 2015 A1 - Floyd, James S A1 - Sitlani, Colleen M A1 - Wiggins, Kerri L A1 - Wallace, Erin A1 - Suchy-Dicey, Astrid A1 - Abbasi, Siddique A A1 - Carnethon, Mercedes R A1 - Siscovick, David S A1 - Sotoodehnia, Nona A1 - Heckbert, Susan R A1 - McKnight, Barbara A1 - Rice, Kenneth M A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Heart Rate KW - Humans KW - Incidence KW - Linear Models KW - Male KW - Myocardial Infarction KW - Outcome Assessment (Health Care) KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Rest KW - Risk Factors KW - Time KW - Washington AB -

OBJECTIVE: Resting heart rate (RHR) is an established predictor of myocardial infarction (MI) and mortality, but the relationship between variation in RHR over a period of several years and health outcomes is unclear. We evaluated the relationship between long-term variation in RHR and the risks of incident MI and mortality among older adults.

METHODS: 1991 subjects without cardiovascular disease from the Cardiovascular Health Study were included. RHR was taken from resting ECGs at the first five annual study visits. RHR mean, trend and variation were estimated with linear regression. Subjects were followed for incident MI and death until December 2010. HRs for RHR mean, trend and variation are reported for differences of 10 bpm, 2 bpm/year and 2 bpm, respectively.

RESULTS: 262 subjects had an incident MI event (13%) and 1326 died (67%) during 12 years of median follow-up. In primary analyses adjusted for cardiovascular risk factors, RHR mean (HR 1.12; 95% CI 1.05 to 1.20) and variation (HR 1.08; 95% CI 1.03 to 1.13) were associated with the risk of death while trend was not. None of the RHR variables were significantly associated with the risk of incident MI events; however, CIs were wide and the MI associations with RHR variables were not significantly different from the mortality associations. Adjusting for additional variables did not affect estimates, and there were no significant interactions with sex.

CONCLUSIONS: Variation in RHR over a period of several years represents a potential predictor of long-term mortality among older persons free of cardiovascular disease.

VL - 101 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25214500?dopt=Abstract ER - TY - JOUR T1 - Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits. JF - Am J Hum Genet Y1 - 2016 A1 - Chami, Nathalie A1 - Chen, Ming-Huei A1 - Slater, Andrew J A1 - Eicher, John D A1 - Evangelou, Evangelos A1 - Tajuddin, Salman M A1 - Love-Gregory, Latisha A1 - Kacprowski, Tim A1 - Schick, Ursula M A1 - Nomura, Akihiro A1 - Giri, Ayush A1 - Lessard, Samuel A1 - Brody, Jennifer A A1 - Schurmann, Claudia A1 - Pankratz, Nathan A1 - Yanek, Lisa R A1 - Manichaikul, Ani A1 - Pazoki, Raha A1 - Mihailov, Evelin A1 - Hill, W David A1 - Raffield, Laura M A1 - Burt, Amber A1 - Bartz, Traci M A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Boerwinkle, Eric A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - O'Donoghue, Michelle L A1 - Crosslin, David R A1 - de Denus, Simon A1 - Dubé, Marie-Pierre A1 - Elliott, Paul A1 - Engström, Gunnar A1 - Evans, Michele K A1 - Floyd, James S A1 - Fornage, Myriam A1 - Gao, He A1 - Greinacher, Andreas A1 - Gudnason, Vilmundur A1 - Hansen, Torben A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Hernesniemi, Jussi A1 - Highland, Heather M A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Irvin, Marguerite R A1 - Kähönen, Mika A1 - Lange, Ethan A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - Li, Jin A1 - Liewald, David C M A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Lu, Yingchang A1 - Lyytikäinen, Leo-Pekka A1 - Mägi, Reedik A1 - Mathias, Rasika A A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mononen, Nina A1 - Nalls, Mike A A1 - Nickerson, Deborah A A1 - Nikus, Kjell A1 - O'Donnell, Chris J A1 - Orho-Melander, Marju A1 - Pedersen, Oluf A1 - Petersmann, Astrid A1 - Polfus, Linda A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Raitoharju, Emma A1 - Richard, Melissa A1 - Rice, Kenneth M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Schmidt, Frank A1 - Smith, Albert Vernon A1 - Starr, John M A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thuesen, Betina H A1 - Torstenson, Eric S A1 - Tracy, Russell P A1 - Tzoulaki, Ioanna A1 - Zakai, Neil A A1 - Vacchi-Suzzi, Caterina A1 - van Duijn, Cornelia M A1 - van Rooij, Frank J A A1 - Cushman, Mary A1 - Deary, Ian J A1 - Velez Edwards, Digna R A1 - Vergnaud, Anne-Claire A1 - Wallentin, Lars A1 - Waterworth, Dawn M A1 - White, Harvey D A1 - Wilson, James G A1 - Zonderman, Alan B A1 - Kathiresan, Sekar A1 - Grarup, Niels A1 - Esko, Tõnu A1 - Loos, Ruth J F A1 - Lange, Leslie A A1 - Faraday, Nauder A1 - Abumrad, Nada A A1 - Edwards, Todd L A1 - Ganesh, Santhi K A1 - Auer, Paul L A1 - Johnson, Andrew D A1 - Reiner, Alexander P A1 - Lettre, Guillaume AB -

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27346685?dopt=Abstract ER - TY - JOUR T1 - Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases. JF - Am J Hum Genet Y1 - 2016 A1 - Tajuddin, Salman M A1 - Schick, Ursula M A1 - Eicher, John D A1 - Chami, Nathalie A1 - Giri, Ayush A1 - Brody, Jennifer A A1 - Hill, W David A1 - Kacprowski, Tim A1 - Li, Jin A1 - Lyytikäinen, Leo-Pekka A1 - Manichaikul, Ani A1 - Mihailov, Evelin A1 - O'Donoghue, Michelle L A1 - Pankratz, Nathan A1 - Pazoki, Raha A1 - Polfus, Linda M A1 - Smith, Albert Vernon A1 - Schurmann, Claudia A1 - Vacchi-Suzzi, Caterina A1 - Waterworth, Dawn M A1 - Evangelou, Evangelos A1 - Yanek, Lisa R A1 - Burt, Amber A1 - Chen, Ming-Huei A1 - van Rooij, Frank J A A1 - Floyd, James S A1 - Greinacher, Andreas A1 - Harris, Tamara B A1 - Highland, Heather M A1 - Lange, Leslie A A1 - Liu, Yongmei A1 - Mägi, Reedik A1 - Nalls, Mike A A1 - Mathias, Rasika A A1 - Nickerson, Deborah A A1 - Nikus, Kjell A1 - Starr, John M A1 - Tardif, Jean-Claude A1 - Tzoulaki, Ioanna A1 - Velez Edwards, Digna R A1 - Wallentin, Lars A1 - Bartz, Traci M A1 - Becker, Lewis C A1 - Denny, Joshua C A1 - Raffield, Laura M A1 - Rioux, John D A1 - Friedrich, Nele A1 - Fornage, Myriam A1 - Gao, He A1 - Hirschhorn, Joel N A1 - Liewald, David C M A1 - Rich, Stephen S A1 - Uitterlinden, Andre A1 - Bastarache, Lisa A1 - Becker, Diane M A1 - Boerwinkle, Eric A1 - de Denus, Simon A1 - Bottinger, Erwin P A1 - Hayward, Caroline A1 - Hofman, Albert A1 - Homuth, Georg A1 - Lange, Ethan A1 - Launer, Lenore J A1 - Lehtimäki, Terho A1 - Lu, Yingchang A1 - Metspalu, Andres A1 - O'Donnell, Chris J A1 - Quarells, Rakale C A1 - Richard, Melissa A1 - Torstenson, Eric S A1 - Taylor, Kent D A1 - Vergnaud, Anne-Claire A1 - Zonderman, Alan B A1 - Crosslin, David R A1 - Deary, Ian J A1 - Dörr, Marcus A1 - Elliott, Paul A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kähönen, Mika A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Slater, Andrew J A1 - Dehghan, Abbas A1 - White, Harvey D A1 - Ganesh, Santhi K A1 - Loos, Ruth J F A1 - Esko, Tõnu A1 - Faraday, Nauder A1 - Wilson, James G A1 - Cushman, Mary A1 - Johnson, Andrew D A1 - Edwards, Todd L A1 - Zakai, Neil A A1 - Lettre, Guillaume A1 - Reiner, Alex P A1 - Auer, Paul L AB -

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27346689?dopt=Abstract ER - TY - JOUR T1 - Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals. JF - Am J Hum Genet Y1 - 2016 A1 - Eicher, John D A1 - Chami, Nathalie A1 - Kacprowski, Tim A1 - Nomura, Akihiro A1 - Chen, Ming-Huei A1 - Yanek, Lisa R A1 - Tajuddin, Salman M A1 - Schick, Ursula M A1 - Slater, Andrew J A1 - Pankratz, Nathan A1 - Polfus, Linda A1 - Schurmann, Claudia A1 - Giri, Ayush A1 - Brody, Jennifer A A1 - Lange, Leslie A A1 - Manichaikul, Ani A1 - Hill, W David A1 - Pazoki, Raha A1 - Elliot, Paul A1 - Evangelou, Evangelos A1 - Tzoulaki, Ioanna A1 - Gao, He A1 - Vergnaud, Anne-Claire A1 - Mathias, Rasika A A1 - Becker, Diane M A1 - Becker, Lewis C A1 - Burt, Amber A1 - Crosslin, David R A1 - Lyytikäinen, Leo-Pekka A1 - Nikus, Kjell A1 - Hernesniemi, Jussi A1 - Kähönen, Mika A1 - Raitoharju, Emma A1 - Mononen, Nina A1 - Raitakari, Olli T A1 - Lehtimäki, Terho A1 - Cushman, Mary A1 - Zakai, Neil A A1 - Nickerson, Deborah A A1 - Raffield, Laura M A1 - Quarells, Rakale A1 - Willer, Cristen J A1 - Peloso, Gina M A1 - Abecasis, Goncalo R A1 - Liu, Dajiang J A1 - Deloukas, Panos A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Erdmann, Jeanette A1 - Fornage, Myriam A1 - Richard, Melissa A1 - Tardif, Jean-Claude A1 - Rioux, John D A1 - Dubé, Marie-Pierre A1 - de Denus, Simon A1 - Lu, Yingchang A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Smith, Albert Vernon A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Gudnason, Vilmundur A1 - Velez Edwards, Digna R A1 - Torstenson, Eric S A1 - Liu, Yongmei A1 - Tracy, Russell P A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Highland, Heather M A1 - Boerwinkle, Eric A1 - Li, Jin A1 - Lange, Ethan A1 - Wilson, James G A1 - Mihailov, Evelin A1 - Mägi, Reedik A1 - Hirschhorn, Joel A1 - Metspalu, Andres A1 - Esko, Tõnu A1 - Vacchi-Suzzi, Caterina A1 - Nalls, Mike A A1 - Zonderman, Alan B A1 - Evans, Michele K A1 - Engström, Gunnar A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - O'Donoghue, Michelle L A1 - Waterworth, Dawn M A1 - Wallentin, Lars A1 - White, Harvey D A1 - Floyd, James S A1 - Bartz, Traci M A1 - Rice, Kenneth M A1 - Psaty, Bruce M A1 - Starr, J M A1 - Liewald, David C M A1 - Hayward, Caroline A1 - Deary, Ian J A1 - Greinacher, Andreas A1 - Völker, Uwe A1 - Thiele, Thomas A1 - Völzke, Henry A1 - van Rooij, Frank J A A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Dehghan, Abbas A1 - Edwards, Todd L A1 - Ganesh, Santhi K A1 - Kathiresan, Sekar A1 - Faraday, Nauder A1 - Auer, Paul L A1 - Reiner, Alex P A1 - Lettre, Guillaume A1 - Johnson, Andrew D AB -

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

VL - 99 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/27346686?dopt=Abstract ER - TY - JOUR T1 - Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis. JF - Am J Hum Genet Y1 - 2016 A1 - Polfus, Linda M A1 - Khajuria, Rajiv K A1 - Schick, Ursula M A1 - Pankratz, Nathan A1 - Pazoki, Raha A1 - Brody, Jennifer A A1 - Chen, Ming-Huei A1 - Auer, Paul L A1 - Floyd, James S A1 - Huang, Jie A1 - Lange, Leslie A1 - van Rooij, Frank J A A1 - Gibbs, Richard A A1 - Metcalf, Ginger A1 - Muzny, Donna A1 - Veeraraghavan, Narayanan A1 - Walter, Klaudia A1 - Chen, Lu A1 - Yanek, Lisa A1 - Becker, Lewis C A1 - Peloso, Gina M A1 - Wakabayashi, Aoi A1 - Kals, Mart A1 - Metspalu, Andres A1 - Esko, Tõnu A1 - Fox, Keolu A1 - Wallace, Robert A1 - Franceschini, Nora A1 - Matijevic, Nena A1 - Rice, Kenneth M A1 - Bartz, Traci M A1 - Lyytikäinen, Leo-Pekka A1 - Kähönen, Mika A1 - Lehtimäki, Terho A1 - Raitakari, Olli T A1 - Li-Gao, Ruifang A1 - Mook-Kanamori, Dennis O A1 - Lettre, Guillaume A1 - van Duijn, Cornelia M A1 - Franco, Oscar H A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Wilson, James G A1 - Psaty, Bruce M A1 - Soranzo, Nicole A1 - Dehghan, Abbas A1 - Boerwinkle, Eric A1 - Zhang, Xiaoling A1 - Johnson, Andrew D A1 - O'Donnell, Christopher J A1 - Johnsen, Jill M A1 - Reiner, Alexander P A1 - Ganesh, Santhi K A1 - Sankaran, Vijay G VL - 99 IS - 3 ER - TY - JOUR T1 - A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. JF - J Med Genet Y1 - 2017 A1 - Noordam, Raymond A1 - Sitlani, Colleen M A1 - Avery, Christy L A1 - Stewart, James D A1 - Gogarten, Stephanie M A1 - Wiggins, Kerri L A1 - Trompet, Stella A1 - Warren, Helen R A1 - Sun, Fangui A1 - Evans, Daniel S A1 - Li, Xiaohui A1 - Li, Jin A1 - Smith, Albert V A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Busch, Evan L A1 - Caulfield, Mark J A1 - Chen, Yii-der I A1 - Cummings, Steven R A1 - Cupples, L Adrienne A1 - Duan, Qing A1 - Franco, Oscar H A1 - Méndez-Giráldez, Rául A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - van Heemst, Diana A1 - Hofman, Albert A1 - Floyd, James S A1 - Kors, Jan A A1 - Launer, Lenore J A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Lange, Leslie A A1 - Lin, Henry J A1 - de Mutsert, Renée A1 - Napier, Melanie D A1 - Newton-Cheh, Christopher A1 - Poulter, Neil A1 - Reiner, Alexander P A1 - Rice, Kenneth M A1 - Roach, Jeffrey A1 - Rodriguez, Carlos J A1 - Rosendaal, Frits R A1 - Sattar, Naveed A1 - Sever, Peter A1 - Seyerle, Amanda A A1 - Slagboom, P Eline A1 - Soliman, Elsayed Z A1 - Sotoodehnia, Nona A1 - Stott, David J A1 - Stürmer, Til A1 - Taylor, Kent D A1 - Thornton, Timothy A A1 - Uitterlinden, André G A1 - Wilhelmsen, Kirk C A1 - Wilson, James G A1 - Gudnason, Vilmundur A1 - Jukema, J Wouter A1 - Laurie, Cathy C A1 - Liu, Yongmei A1 - Mook-Kanamori, Dennis O A1 - Munroe, Patricia B A1 - Rotter, Jerome I A1 - Vasan, Ramachandran S A1 - Psaty, Bruce M A1 - Stricker, Bruno H A1 - Whitsel, Eric A AB -

BACKGROUND: Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals.

METHODS AND RESULTS: We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β=56.3, pinteraction=3.9e(-9)) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e(-8)). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=9.3, pinteraction=2.55e(-8)). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.

CONCLUSIONS: Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.

VL - 54 IS - 5 ER - TY - JOUR T1 - Genome-wide Trans-ethnic Meta-analysis Identifies Seven Genetic Loci Influencing Erythrocyte Traits and a Role for RBPMS in Erythropoiesis. JF - Am J Hum Genet Y1 - 2017 A1 - van Rooij, Frank J A A1 - Qayyum, Rehan A1 - Smith, Albert V A1 - Zhou, Yi A1 - Trompet, Stella A1 - Tanaka, Toshiko A1 - Keller, Margaux F A1 - Chang, Li-Ching A1 - Schmidt, Helena A1 - Yang, Min-Lee A1 - Chen, Ming-Huei A1 - Hayes, James A1 - Johnson, Andrew D A1 - Yanek, Lisa R A1 - Mueller, Christian A1 - Lange, Leslie A1 - Floyd, James S A1 - Ghanbari, Mohsen A1 - Zonderman, Alan B A1 - Jukema, J Wouter A1 - Hofman, Albert A1 - van Duijn, Cornelia M A1 - Desch, Karl C A1 - Saba, Yasaman A1 - Ozel, Ayse B A1 - Snively, Beverly M A1 - Wu, Jer-Yuarn A1 - Schmidt, Reinhold A1 - Fornage, Myriam A1 - Klein, Robert J A1 - Fox, Caroline S A1 - Matsuda, Koichi A1 - Kamatani, Naoyuki A1 - Wild, Philipp S A1 - Stott, David J A1 - Ford, Ian A1 - Slagboom, P Eline A1 - Yang, Jaden A1 - Chu, Audrey Y A1 - Lambert, Amy J A1 - Uitterlinden, André G A1 - Franco, Oscar H A1 - Hofer, Edith A1 - Ginsburg, David A1 - Hu, Bella A1 - Keating, Brendan A1 - Schick, Ursula M A1 - Brody, Jennifer A A1 - Li, Jun Z A1 - Chen, Zhao A1 - Zeller, Tanja A1 - Guralnik, Jack M A1 - Chasman, Daniel I A1 - Peters, Luanne L A1 - Kubo, Michiaki A1 - Becker, Diane M A1 - Li, Jin A1 - Eiriksdottir, Gudny A1 - Rotter, Jerome I A1 - Levy, Daniel A1 - Grossmann, Vera A1 - Patel, Kushang V A1 - Chen, Chien-Hsiun A1 - Ridker, Paul M A1 - Tang, Hua A1 - Launer, Lenore J A1 - Rice, Kenneth M A1 - Li-Gao, Ruifang A1 - Ferrucci, Luigi A1 - Evans, Michelle K A1 - Choudhuri, Avik A1 - Trompouki, Eirini A1 - Abraham, Brian J A1 - Yang, Song A1 - Takahashi, Atsushi A1 - Kamatani, Yoichiro A1 - Kooperberg, Charles A1 - Harris, Tamara B A1 - Jee, Sun Ha A1 - Coresh, Josef A1 - Tsai, Fuu-Jen A1 - Longo, Dan L A1 - Chen, Yuan-Tsong A1 - Felix, Janine F A1 - Yang, Qiong A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Becker, Lewis C A1 - Mook-Kanamori, Dennis O A1 - Wilson, James G A1 - Gudnason, Vilmundur A1 - O'Donnell, Christopher J A1 - Dehghan, Abbas A1 - Cupples, L Adrienne A1 - Nalls, Michael A A1 - Morris, Andrew P A1 - Okada, Yukinori A1 - Reiner, Alexander P A1 - Zon, Leonard I A1 - Ganesh, Santhi K AB -

Genome-wide association studies (GWASs) have identified loci for erythrocyte traits in primarily European ancestry populations. We conducted GWAS meta-analyses of six erythrocyte traits in 71,638 individuals from European, East Asian, and African ancestries using a Bayesian approach to account for heterogeneity in allelic effects and variation in the structure of linkage disequilibrium between ethnicities. We identified seven loci for erythrocyte traits including a locus (RBPMS/GTF2E2) associated with mean corpuscular hemoglobin and mean corpuscular volume. Statistical fine-mapping at this locus pointed to RBPMS at this locus and excluded nearby GTF2E2. Using zebrafish morpholino to evaluate loss of function, we observed a strong in vivo erythropoietic effect for RBPMS but not for GTF2E2, supporting the statistical fine-mapping at this locus and demonstrating that RBPMS is a regulator of erythropoiesis. Our findings show the utility of trans-ethnic GWASs for discovery and characterization of genetic loci influencing hematologic traits.

VL - 100 IS - 1 ER - TY - JOUR T1 - Generalization and fine mapping of red blood cell trait genetic associations to multi-ethnic populations: The PAGE Study. JF - Am J Hematol Y1 - 2018 A1 - Jo Hodonsky, Chani A1 - Schurmann, Claudia A1 - Schick, Ursula M A1 - Kocarnik, Jonathan A1 - Tao, Ran A1 - van Rooij, Frank Ja A1 - Wassel, Christina A1 - Buyske, Steve A1 - Fornage, Myriam A1 - Hindorff, Lucia A A1 - Floyd, James S A1 - Ganesh, Santhi K A1 - Lin, Dan-Yu A1 - North, Kari E A1 - Reiner, Alex P A1 - Loos, Ruth Jf A1 - Kooperberg, Charles A1 - Avery, Christy L AB -

Red blood cell (RBC) traits provide insight into a wide range of physiological states and exhibit moderate to high heritability, making them excellent candidates for genetic studies to inform underlying biologic mechanisms. Previous RBC trait genome-wide association studies were performed primarily in European- or Asian-ancestry populations, missing opportunities to inform understanding of RBC genetic architecture in diverse populations and reduce intervals surrounding putative functional SNPs through fine-mapping. Here, we report the first fine-mapping of six correlated (Pearson's r range: |0.04 - 0.92|) RBC traits in up to 19,036 African Americans and 19,562 Hispanic/Latinos participants of the Population Architecture using Genomics and Epidemiology (PAGE) consortium. Trans-ethnic meta-analysis of race/ethnic- and study-specific estimates for approximately 11,000 SNPs flanking 13 previously identified association signals as well as 150,000 additional array-wide SNPs was performed using inverse-variance meta-analysis after adjusting for study and clinical covariates. Approximately half of previously reported index SNP-RBC trait associations generalized to the trans-ethnic study population (p<1.7x10 ); previously unreported independent association signals within the ABO region reinforce the potential for multiple functional variants affecting the same locus. Trans-ethnic fine-mapping did not reveal additional signals at the HFE locus independent of the known functional variants. Finally, we identified a potential novel association in the Hispanic/Latino study population at the HECTD4/RPL6 locus for RBC count (p=1.9x10 ). The identification of a previously unknown association, generalization of a large proportion of known association signals, and refinement of known association signals all exemplify the benefits of genetic studies in diverse populations. This article is protected by copyright. All rights reserved.

ER - TY - JOUR T1 - Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry. JF - Pharmacogenomics J Y1 - 2018 A1 - Irvin, Marguerite R A1 - Sitlani, Colleen M A1 - Noordam, Raymond A1 - Avery, Christie L A1 - Bis, Joshua C A1 - Floyd, James S A1 - Li, Jin A1 - Limdi, Nita A A1 - Srinivasasainagendra, Vinodh A1 - Stewart, James A1 - de Mutsert, Renée A1 - Mook-Kanamori, Dennis O A1 - Lipovich, Leonard A1 - Kleinbrink, Erica L A1 - Smith, Albert A1 - Bartz, Traci M A1 - Whitsel, Eric A A1 - Uitterlinden, André G A1 - Wiggins, Kerri L A1 - Wilson, James G A1 - Zhi, Degui A1 - Stricker, Bruno H A1 - Rotter, Jerome I A1 - Arnett, Donna K A1 - Psaty, Bruce M A1 - Lange, Leslie A AB -

We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.

ER - TY - JOUR T1 - Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease. JF - Circulation Y1 - 2019 A1 - Agha, Golareh A1 - Mendelson, Michael M A1 - Ward-Caviness, Cavin K A1 - Joehanes, Roby A1 - Huan, Tianxiao A1 - Gondalia, Rahul A1 - Salfati, Elias A1 - Brody, Jennifer A A1 - Fiorito, Giovanni A1 - Bressler, Jan A1 - Chen, Brian H A1 - Ligthart, Symen A1 - Guarrera, Simonetta A1 - Colicino, Elena A1 - Just, Allan C A1 - Wahl, Simone A1 - Gieger, Christian A1 - Vandiver, Amy R A1 - Tanaka, Toshiko A1 - Hernandez, Dena G A1 - Pilling, Luke C A1 - Singleton, Andrew B A1 - Sacerdote, Carlotta A1 - Krogh, Vittorio A1 - Panico, Salvatore A1 - Tumino, Rosario A1 - Li, Yun A1 - Zhang, Guosheng A1 - Stewart, James D A1 - Floyd, James S A1 - Wiggins, Kerri L A1 - Rotter, Jerome I A1 - Multhaup, Michael A1 - Bakulski, Kelly A1 - Horvath, Steven A1 - Tsao, Philip S A1 - Absher, Devin M A1 - Vokonas, Pantel A1 - Hirschhorn, Joel A1 - Fallin, M Daniele A1 - Liu, Chunyu A1 - Bandinelli, Stefania A1 - Boerwinkle, Eric A1 - Dehghan, Abbas A1 - Schwartz, Joel D A1 - Psaty, Bruce M A1 - Feinberg, Andrew P A1 - Hou, Lifang A1 - Ferrucci, Luigi A1 - Sotoodehnia, Nona A1 - Matullo, Giuseppe A1 - Peters, Annette A1 - Fornage, Myriam A1 - Assimes, Themistocles L A1 - Whitsel, Eric A A1 - Levy, Daniel A1 - Baccarelli, Andrea A KW - Adult KW - Aged KW - Cohort Studies KW - Coronary Disease KW - CpG Islands KW - DNA Methylation KW - Europe KW - Female KW - Genome-Wide Association Study KW - Humans KW - Incidence KW - Leukocytes KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Population Groups KW - Prognosis KW - Prospective Studies KW - Risk KW - United States AB -

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

VL - 140 IS - 8 ER - TY - JOUR T1 - Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group. JF - Am J Hypertens Y1 - 2019 A1 - Irvin, Marguerite R A1 - Sitlani, Colleen M A1 - Floyd, James S A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Wiggins, Kerri L A1 - Whitsel, Eric A A1 - Stürmer, Til A1 - Stewart, James A1 - Raffield, Laura A1 - Sun, Fangui A1 - Liu, Ching-Ti A1 - Xu, Hanfei A1 - Cupples, Adrienne L A1 - Tanner, Rikki M A1 - Rossing, Peter A1 - Smith, Albert A1 - Zilhão, Nuno R A1 - Launer, Lenore J A1 - Noordam, Raymond A1 - Rotter, Jerome I A1 - Yao, Jie A1 - Li, Xiaohui A1 - Guo, Xiuqing A1 - Limdi, Nita A1 - Sundaresan, Aishwarya A1 - Lange, Leslie A1 - Correa, Adolfo A1 - Stott, David J A1 - Ford, Ian A1 - Jukema, J Wouter A1 - Gudnason, Vilmundur A1 - Mook-Kanamori, Dennis O A1 - Trompet, Stella A1 - Palmas, Walter A1 - Warren, Helen R A1 - Hellwege, Jacklyn N A1 - Giri, Ayush A1 - O'donnell, Christopher A1 - Hung, Adriana M A1 - Edwards, Todd L A1 - Ahluwalia, Tarunveer S A1 - Arnett, Donna K A1 - Avery, Christy L KW - Aged KW - Antihypertensive Agents KW - Black or African American KW - Blood Pressure KW - Case-Control Studies KW - DNA (Cytosine-5-)-Methyltransferases KW - DNA Methyltransferase 3A KW - DNA-Binding Proteins KW - Drug Resistance KW - Dystrophin-Associated Proteins KW - Europe KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Myosin Heavy Chains KW - Myosin Type V KW - Neuropeptides KW - Pharmacogenetics KW - Pharmacogenomic Variants KW - Polymorphism, Single Nucleotide KW - Risk Assessment KW - Risk Factors KW - Transcription Factors KW - United States KW - White People AB -

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

METHODS: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

VL - 32 IS - 12 ER - TY - JOUR T1 - Genomewide Association Study of Statin-Induced Myopathy in Patients Recruited Using the UK Clinical Practice Research Datalink. JF - Clin Pharmacol Ther Y1 - 2019 A1 - Carr, Daniel F A1 - Francis, Ben A1 - Jorgensen, Andrea L A1 - Zhang, Eunice A1 - Chinoy, Hector A1 - Heckbert, Susan R A1 - Bis, Joshua C A1 - Brody, Jennifer A A1 - Floyd, James S A1 - Psaty, Bruce M A1 - Molokhia, Mariam A1 - Lapeyre-Mestre, Maryse A1 - Conforti, Anita A1 - Alfirevic, Ana A1 - van Staa, Tjeerd A1 - Pirmohamed, Munir KW - Adverse Drug Reaction Reporting Systems KW - Case-Control Studies KW - Databases, Factual KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Liver-Specific Organic Anion Transporter 1 KW - Muscular Diseases KW - Pharmacogenomic Variants KW - Polymorphism, Single Nucleotide KW - Reproducibility of Results KW - Risk Factors KW - Severity of Illness Index KW - United Kingdom AB -

Statins can be associated with myopathy. We have undertaken a genomewide association study (GWAS) to discover and validate genetic risk factors for statin-induced myopathy in a "real-world" setting. One hundred thirty-five patients with statin myopathy recruited via the UK Clinical Practice Research Datalink were genotyped using the Illumina OmniExpress Exome version 1.0 Bead Chip and compared with the Wellcome Trust Case-Control Consortium (n = 2,501). Nominally statistically significant single nucleotide polymorphism (SNP) signals in the GWAS (P < 5 × 10 ) were further evaluated in several independent cohorts (comprising 332 cases and 449 drug-tolerant controls). Only one (rs4149056/c.521C>T in the SLCO1B1 gene) SNP was genomewide significant in the severe myopathy (creatine kinase > 10 × upper limit of normal or rhabdomyolysis) group (P = 2.55 × 10 ; odds ratio 5.15; 95% confidence interval 3.13-8.45). The association with SLCO1B1 was present for several statins and replicated in the independent validation cohorts. The data highlight the role of SLCO1B1 c.521C>T SNP as a replicable genetic risk factor for statin myopathy. No other novel genetic risk factors with a similar effect size were identified.

VL - 106 IS - 6 ER - TY - JOUR T1 - Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. JF - Nat Genet Y1 - 2019 A1 - Bentley, Amy R A1 - Sung, Yun J A1 - Brown, Michael R A1 - Winkler, Thomas W A1 - Kraja, Aldi T A1 - Ntalla, Ioanna A1 - Schwander, Karen A1 - Chasman, Daniel I A1 - Lim, Elise A1 - Deng, Xuan A1 - Guo, Xiuqing A1 - Liu, Jingmin A1 - Lu, Yingchang A1 - Cheng, Ching-Yu A1 - Sim, Xueling A1 - Vojinovic, Dina A1 - Huffman, Jennifer E A1 - Musani, Solomon K A1 - Li, Changwei A1 - Feitosa, Mary F A1 - Richard, Melissa A A1 - Noordam, Raymond A1 - Baker, Jenna A1 - Chen, Guanjie A1 - Aschard, Hugues A1 - Bartz, Traci M A1 - Ding, Jingzhong A1 - Dorajoo, Rajkumar A1 - Manning, Alisa K A1 - Rankinen, Tuomo A1 - Smith, Albert V A1 - Tajuddin, Salman M A1 - Zhao, Wei A1 - Graff, Mariaelisa A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Chai, Jin Fang A1 - Chen, Xu A1 - Divers, Jasmin A1 - Evangelou, Evangelos A1 - Gao, Chuan A1 - Goel, Anuj A1 - Hagemeijer, Yanick A1 - Harris, Sarah E A1 - Hartwig, Fernando P A1 - He, Meian A1 - Horimoto, Andrea R V R A1 - Hsu, Fang-Chi A1 - Hung, Yi-Jen A1 - Jackson, Anne U A1 - Kasturiratne, Anuradhani A1 - Komulainen, Pirjo A1 - Kuhnel, Brigitte A1 - Leander, Karin A1 - Lin, Keng-Hung A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Matoba, Nana A1 - Nolte, Ilja M A1 - Pietzner, Maik A1 - Prins, Bram A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Said, M Abdullah A1 - Schupf, Nicole A1 - Scott, Robert A A1 - Sofer, Tamar A1 - Stančáková, Alena A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Varga, Tibor V A1 - Wang, Tzung-Dau A1 - Wang, Yajuan A1 - Ware, Erin B A1 - Wen, Wanqing A1 - Xiang, Yong-Bing A1 - Yanek, Lisa R A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Adeyemo, Adebowale A1 - Afaq, Saima A1 - Amin, Najaf A1 - Amini, Marzyeh A1 - Arking, Dan E A1 - Arzumanyan, Zorayr A1 - Aung, Tin A1 - Ballantyne, Christie A1 - Barr, R Graham A1 - Bielak, Lawrence F A1 - Boerwinkle, Eric A1 - Bottinger, Erwin P A1 - Broeckel, Ulrich A1 - Brown, Morris A1 - Cade, Brian E A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Charumathi, Sabanayagam A1 - Chen, Yii-Der Ida A1 - Christensen, Kaare A1 - Concas, Maria Pina A1 - Connell, John M A1 - de Las Fuentes, Lisa A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Doumatey, Ayo A1 - Duan, Qing A1 - Eaton, Charles B A1 - Eppinga, Ruben N A1 - Faul, Jessica D A1 - Floyd, James S A1 - Forouhi, Nita G A1 - Forrester, Terrence A1 - Friedlander, Yechiel A1 - Gandin, Ilaria A1 - Gao, He A1 - Ghanbari, Mohsen A1 - Gharib, Sina A A1 - Gigante, Bruna A1 - Giulianini, Franco A1 - Grabe, Hans J A1 - Gu, C Charles A1 - Harris, Tamara B A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Hirata, Makoto A1 - Hixson, James E A1 - Ikram, M Arfan A1 - Jia, Yucheng A1 - Joehanes, Roby A1 - Johnson, Craig A1 - Jonas, Jost Bruno A1 - Justice, Anne E A1 - Katsuya, Tomohiro A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Krieger, Jose E A1 - Kritchevsky, Stephen B A1 - Kubo, Michiaki A1 - Kuusisto, Johanna A1 - Lakka, Timo A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Lehne, Benjamin A1 - Lewis, Cora E A1 - Li, Yize A1 - Liang, Jingjing A1 - Lin, Shiow A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Loh, Marie A1 - Lohman, Kurt K A1 - Louie, Tin A1 - Luzzi, Anna A1 - Mägi, Reedik A1 - Mahajan, Anubha A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Milaneschi, Yuri A1 - Milani, Lili A1 - Mohlke, Karen L A1 - Momozawa, Yukihide A1 - Morris, Andrew P A1 - Murray, Alison D A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - North, Kari E A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Papanicolau, George J A1 - Pedersen, Nancy L A1 - Peters, Annette A1 - Peyser, Patricia A A1 - Polasek, Ozren A1 - Poulter, Neil A1 - Raitakari, Olli T A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Robinson, Jennifer G A1 - Rose, Lynda M A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Schmidt, Carsten O A1 - Schreiner, Pamela J A1 - Scott, William R A1 - Sever, Peter A1 - Shi, Yuan A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Snieder, Harold A1 - Starr, John M A1 - Strauch, Konstantin A1 - Stringham, Heather M A1 - Tan, Nicholas Y Q A1 - Tang, Hua A1 - Taylor, Kent D A1 - Teo, Yik Ying A1 - Tham, Yih Chung A1 - Tiemeier, Henning A1 - Turner, Stephen T A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Waldenberger, Melanie A1 - Wang, Heming A1 - Wang, Lan A1 - Wang, Lihua A1 - Wei, Wen Bin A1 - Williams, Christine A A1 - Wilson, Gregory A1 - Wojczynski, Mary K A1 - Yao, Jie A1 - Young, Kristin A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhou, Jie A1 - Zonderman, Alan B A1 - Becker, Diane M A1 - Boehnke, Michael A1 - Bowden, Donald W A1 - Chambers, John C A1 - Cooper, Richard S A1 - de Faire, Ulf A1 - Deary, Ian J A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Farrall, Martin A1 - Franks, Paul W A1 - Freedman, Barry I A1 - Froguel, Philippe A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Horta, Bernardo L A1 - Juang, Jyh-Ming Jimmy A1 - Kamatani, Yoichiro A1 - Kammerer, Candace M A1 - Kato, Norihiro A1 - Kooner, Jaspal S A1 - Laakso, Markku A1 - Laurie, Cathy C A1 - Lee, I-Te A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - Oldehinkel, Albertine J A1 - Penninx, Brenda W J H A1 - Pereira, Alexandre C A1 - Rauramaa, Rainer A1 - Redline, Susan A1 - Samani, Nilesh J A1 - Scott, James A1 - Shu, Xiao-Ou A1 - van der Harst, Pim A1 - Wagenknecht, Lynne E A1 - Wang, Jun-Sing A1 - Wang, Ya Xing A1 - Wareham, Nicholas J A1 - Watkins, Hugh A1 - Weir, David R A1 - Wickremasinghe, Ananda R A1 - Wu, Tangchun A1 - Zeggini, Eleftheria A1 - Zheng, Wei A1 - Bouchard, Claude A1 - Evans, Michele K A1 - Gudnason, Vilmundur A1 - Kardia, Sharon L R A1 - Liu, Yongmei A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - van Dam, Rob M A1 - Mook-Kanamori, Dennis O A1 - Fornage, Myriam A1 - Province, Michael A A1 - Kelly, Tanika N A1 - Fox, Ervin R A1 - Hayward, Caroline A1 - van Duijn, Cornelia M A1 - Tai, E Shyong A1 - Wong, Tien Yin A1 - Loos, Ruth J F A1 - Franceschini, Nora A1 - Rotter, Jerome I A1 - Zhu, Xiaofeng A1 - Bierut, Laura J A1 - Gauderman, W James A1 - Rice, Kenneth A1 - Munroe, Patricia B A1 - Morrison, Alanna C A1 - Rao, Dabeeru C A1 - Rotimi, Charles N A1 - Cupples, L Adrienne AB -

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

VL - 51 IS - 4 ER - TY - JOUR T1 - Pharmacogenomics of statin-related myopathy: Meta-analysis of rare variants from whole-exome sequencing. JF - PLoS One Y1 - 2019 A1 - Floyd, James S A1 - Bloch, Katarzyna M A1 - Brody, Jennifer A A1 - Maroteau, Cyrielle A1 - Siddiqui, Moneeza K A1 - Gregory, Richard A1 - Carr, Daniel F A1 - Molokhia, Mariam A1 - Liu, Xiaoming A1 - Bis, Joshua C A1 - Ahmed, Ammar A1 - Liu, Xuan A1 - Hallberg, Pär A1 - Yue, Qun-Ying A1 - Magnusson, Patrik K E A1 - Brisson, Diane A1 - Wiggins, Kerri L A1 - Morrison, Alanna C A1 - Khoury, Etienne A1 - McKeigue, Paul A1 - Stricker, Bruno H A1 - Lapeyre-Mestre, Maryse A1 - Heckbert, Susan R A1 - Gallagher, Arlene M A1 - Chinoy, Hector A1 - Gibbs, Richard A A1 - Bondon-Guitton, Emmanuelle A1 - Tracy, Russell A1 - Boerwinkle, Eric A1 - Gaudet, Daniel A1 - Conforti, Anita A1 - van Staa, Tjeerd A1 - Sitlani, Colleen M A1 - Rice, Kenneth M A1 - Maitland-van der Zee, Anke-Hilse A1 - Wadelius, Mia A1 - Morris, Andrew P A1 - Pirmohamed, Munir A1 - Palmer, Colin A N A1 - Psaty, Bruce M A1 - Alfirevic, Ana AB -

AIMS: Statin-related myopathy (SRM), which includes rhabdomyolysis, is an uncommon but important adverse drug reaction because the number of people prescribed statins world-wide is large. Previous association studies of common genetic variants have had limited success in identifying a genetic basis for this adverse drug reaction. We conducted a multi-site whole-exome sequencing study to investigate whether rare coding variants confer an increased risk of SRM.

METHODS AND RESULTS: SRM 3-5 cases (N = 505) and statin treatment-tolerant controls (N = 2047) were recruited from multiple sites in North America and Europe. SRM 3-5 was defined as symptoms consistent with muscle injury and an elevated creatine phosphokinase level >4 times upper limit of normal without another likely cause of muscle injury. Whole-exome sequencing and variant calling was coordinated from two analysis centres, and results of single-variant and gene-based burden tests were meta-analysed. No genome-wide significant associations were identified. Given the large number of cases, we had 80% power to identify a variant with minor allele frequency of 0.01 that increases the risk of SRM 6-fold at genome-wide significance.

CONCLUSIONS: In this large whole-exome sequencing study of severe statin-related muscle injury conducted to date, we did not find evidence that rare coding variants are responsible for this adverse drug reaction. Larger sample sizes would be required to identify rare variants with small effects, but it is unclear whether such findings would be clinically actionable.

VL - 14 IS - 6 ER - TY - JOUR T1 - Inherited causes of clonal haematopoiesis in 97,691 whole genomes. JF - Nature Y1 - 2020 A1 - Bick, Alexander G A1 - Weinstock, Joshua S A1 - Nandakumar, Satish K A1 - Fulco, Charles P A1 - Bao, Erik L A1 - Zekavat, Seyedeh M A1 - Szeto, Mindy D A1 - Liao, Xiaotian A1 - Leventhal, Matthew J A1 - Nasser, Joseph A1 - Chang, Kyle A1 - Laurie, Cecelia A1 - Burugula, Bala Bharathi A1 - Gibson, Christopher J A1 - Lin, Amy E A1 - Taub, Margaret A A1 - Aguet, Francois A1 - Ardlie, Kristin A1 - Mitchell, Braxton D A1 - Barnes, Kathleen C A1 - Moscati, Arden A1 - Fornage, Myriam A1 - Redline, Susan A1 - Psaty, Bruce M A1 - Silverman, Edwin K A1 - Weiss, Scott T A1 - Palmer, Nicholette D A1 - Vasan, Ramachandran S A1 - Burchard, Esteban G A1 - Kardia, Sharon L R A1 - He, Jiang A1 - Kaplan, Robert C A1 - Smith, Nicholas L A1 - Arnett, Donna K A1 - Schwartz, David A A1 - Correa, Adolfo A1 - de Andrade, Mariza A1 - Guo, Xiuqing A1 - Konkle, Barbara A A1 - Custer, Brian A1 - Peralta, Juan M A1 - Gui, Hongsheng A1 - Meyers, Deborah A A1 - McGarvey, Stephen T A1 - Chen, Ida Yii-Der A1 - Shoemaker, M Benjamin A1 - Peyser, Patricia A A1 - Broome, Jai G A1 - Gogarten, Stephanie M A1 - Wang, Fei Fei A1 - Wong, Quenna A1 - Montasser, May E A1 - Daya, Michelle A1 - Kenny, Eimear E A1 - North, Kari E A1 - Launer, Lenore J A1 - Cade, Brian E A1 - Bis, Joshua C A1 - Cho, Michael H A1 - Lasky-Su, Jessica A1 - Bowden, Donald W A1 - Cupples, L Adrienne A1 - Mak, Angel C Y A1 - Becker, Lewis C A1 - Smith, Jennifer A A1 - Kelly, Tanika N A1 - Aslibekyan, Stella A1 - Heckbert, Susan R A1 - Tiwari, Hemant K A1 - Yang, Ivana V A1 - Heit, John A A1 - Lubitz, Steven A A1 - Johnsen, Jill M A1 - Curran, Joanne E A1 - Wenzel, Sally E A1 - Weeks, Daniel E A1 - Rao, Dabeeru C A1 - Darbar, Dawood A1 - Moon, Jee-Young A1 - Tracy, Russell P A1 - Buth, Erin J A1 - Rafaels, Nicholas A1 - Loos, Ruth J F A1 - Durda, Peter A1 - Liu, Yongmei A1 - Hou, Lifang A1 - Lee, Jiwon A1 - Kachroo, Priyadarshini A1 - Freedman, Barry I A1 - Levy, Daniel A1 - Bielak, Lawrence F A1 - Hixson, James E A1 - Floyd, James S A1 - Whitsel, Eric A A1 - Ellinor, Patrick T A1 - Irvin, Marguerite R A1 - Fingerlin, Tasha E A1 - Raffield, Laura M A1 - Armasu, Sebastian M A1 - Wheeler, Marsha M A1 - Sabino, Ester C A1 - Blangero, John A1 - Williams, L Keoki A1 - Levy, Bruce D A1 - Sheu, Wayne Huey-Herng A1 - Roden, Dan M A1 - Boerwinkle, Eric A1 - Manson, JoAnn E A1 - Mathias, Rasika A A1 - Desai, Pinkal A1 - Taylor, Kent D A1 - Johnson, Andrew D A1 - Auer, Paul L A1 - Kooperberg, Charles A1 - Laurie, Cathy C A1 - Blackwell, Thomas W A1 - Smith, Albert V A1 - Zhao, Hongyu A1 - Lange, Ethan A1 - Lange, Leslie A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Wilson, James G A1 - Scheet, Paul A1 - Kitzman, Jacob O A1 - Lander, Eric S A1 - Engreitz, Jesse M A1 - Ebert, Benjamin L A1 - Reiner, Alexander P A1 - Jaiswal, Siddhartha A1 - Abecasis, Goncalo A1 - Sankaran, Vijay G A1 - Kathiresan, Sekar A1 - Natarajan, Pradeep AB -

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

VL - 586 IS - 7831 ER - TY - JOUR T1 - Mitochondrial DNA copy number can influence mortality and cardiovascular disease via methylation of nuclear DNA CpGs. JF - Genome Med Y1 - 2020 A1 - Castellani, Christina A A1 - Longchamps, Ryan J A1 - Sumpter, Jason A A1 - Newcomb, Charles E A1 - Lane, John A A1 - Grove, Megan L A1 - Bressler, Jan A1 - Brody, Jennifer A A1 - Floyd, James S A1 - Bartz, Traci M A1 - Taylor, Kent D A1 - Wang, Penglong A1 - Tin, Adrienne A1 - Coresh, Josef A1 - Pankow, James S A1 - Fornage, Myriam A1 - Guallar, Eliseo A1 - O'Rourke, Brian A1 - Pankratz, Nathan A1 - Liu, Chunyu A1 - Levy, Daniel A1 - Sotoodehnia, Nona A1 - Boerwinkle, Eric A1 - Arking, Dan E AB -

BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) has been associated with a variety of aging-related diseases, including all-cause mortality. However, the mechanism by which mtDNA-CN influences disease is not currently understood. One such mechanism may be through regulation of nuclear gene expression via the modification of nuclear DNA (nDNA) methylation.

METHODS: To investigate this hypothesis, we assessed the relationship between mtDNA-CN and nDNA methylation in 2507 African American (AA) and European American (EA) participants from the Atherosclerosis Risk in Communities (ARIC) study. To validate our findings, we assayed an additional 2528 participants from the Cardiovascular Health Study (CHS) (N = 533) and Framingham Heart Study (FHS) (N = 1995). We further assessed the effect of experimental modification of mtDNA-CN through knockout of TFAM, a regulator of mtDNA replication, via CRISPR-Cas9.

RESULTS: Thirty-four independent CpGs were associated with mtDNA-CN at genome-wide significance (P < 5 × 10). Meta-analysis across all cohorts identified six mtDNA-CN-associated CpGs at genome-wide significance (P < 5 × 10). Additionally, over half of these CpGs were associated with phenotypes known to be associated with mtDNA-CN, including coronary heart disease, cardiovascular disease, and mortality. Experimental modification of mtDNA-CN demonstrated that modulation of mtDNA-CN results in changes in nDNA methylation and gene expression of specific CpGs and nearby transcripts. Strikingly, the "neuroactive ligand receptor interaction" KEGG pathway was found to be highly overrepresented in the ARIC cohort (P = 5.24 × 10), as well as the TFAM knockout methylation (P = 4.41 × 10) and expression (P = 4.30 × 10) studies.

CONCLUSIONS: These results demonstrate that changes in mtDNA-CN influence nDNA methylation at specific loci and result in differential expression of specific genes that may impact human health and disease via altered cell signaling.

VL - 12 IS - 1 ER - TY - JOUR T1 - The Polygenic and Monogenic Basis of Blood Traits and Diseases. JF - Cell Y1 - 2020 A1 - Vuckovic, Dragana A1 - Bao, Erik L A1 - Akbari, Parsa A1 - Lareau, Caleb A A1 - Mousas, Abdou A1 - Jiang, Tao A1 - Chen, Ming-Huei A1 - Raffield, Laura M A1 - Tardaguila, Manuel A1 - Huffman, Jennifer E A1 - Ritchie, Scott C A1 - Megy, Karyn A1 - Ponstingl, Hannes A1 - Penkett, Christopher J A1 - Albers, Patrick K A1 - Wigdor, Emilie M A1 - Sakaue, Saori A1 - Moscati, Arden A1 - Manansala, Regina A1 - Lo, Ken Sin A1 - Qian, Huijun A1 - Akiyama, Masato A1 - Bartz, Traci M A1 - Ben-Shlomo, Yoav A1 - Beswick, Andrew A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Brody, Jennifer A A1 - van Rooij, Frank J A A1 - Chitrala, Kumaraswamy N A1 - Wilson, Peter W F A1 - Choquet, Helene A1 - Danesh, John A1 - Di Angelantonio, Emanuele A1 - Dimou, Niki A1 - Ding, Jingzhong A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Evans, Michele K A1 - Felix, Stephan B A1 - Floyd, James S A1 - Broer, Linda A1 - Grarup, Niels A1 - Guo, Michael H A1 - Guo, Qi A1 - Greinacher, Andreas A1 - Haessler, Jeff A1 - Hansen, Torben A1 - Howson, Joanna M M A1 - Huang, Wei A1 - Jorgenson, Eric A1 - Kacprowski, Tim A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Karthikeyan, Savita A1 - Koskeridis, Fotios A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Lyytikäinen, Leo-Pekka A1 - Manichaikul, Ani A1 - Matsuda, Koichi A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Murakami, Yoshinori A1 - Nadkarni, Girish N A1 - Nikus, Kjell A1 - Pankratz, Nathan A1 - Pedersen, Oluf A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Rich, Stephen S A1 - Rodriguez, Benjamin A T A1 - Rosen, Jonathan D A1 - Rotter, Jerome I A1 - Schubert, Petra A1 - Spracklen, Cassandra N A1 - Surendran, Praveen A1 - Tang, Hua A1 - Tardif, Jean-Claude A1 - Ghanbari, Mohsen A1 - Völker, Uwe A1 - Völzke, Henry A1 - Watkins, Nicholas A A1 - Weiss, Stefan A1 - Cai, Na A1 - Kundu, Kousik A1 - Watt, Stephen B A1 - Walter, Klaudia A1 - Zonderman, Alan B A1 - Cho, Kelly A1 - Li, Yun A1 - Loos, Ruth J F A1 - Knight, Julian C A1 - Georges, Michel A1 - Stegle, Oliver A1 - Evangelou, Evangelos A1 - Okada, Yukinori A1 - Roberts, David J A1 - Inouye, Michael A1 - Johnson, Andrew D A1 - Auer, Paul L A1 - Astle, William J A1 - Reiner, Alexander P A1 - Butterworth, Adam S A1 - Ouwehand, Willem H A1 - Lettre, Guillaume A1 - Sankaran, Vijay G A1 - Soranzo, Nicole AB -

Blood cells play essential roles in human health, underpinning physiological processes such as immunity, oxygen transport, and clotting, which when perturbed cause a significant global health burden. Here we integrate data from UK Biobank and a large-scale international collaborative effort, including data for 563,085 European ancestry participants, and discover 5,106 new genetic variants independently associated with 29 blood cell phenotypes covering a range of variation impacting hematopoiesis. We holistically characterize the genetic architecture of hematopoiesis, assess the relevance of the omnigenic model to blood cell phenotypes, delineate relevant hematopoietic cell states influenced by regulatory genetic variants and gene networks, identify novel splice-altering variants mediating the associations, and assess the polygenic prediction potential for blood traits and clinical disorders at the interface of complex and Mendelian genetics. These results show the power of large-scale blood cell trait GWAS to interrogate clinically meaningful variants across a wide allelic spectrum of human variation.

VL - 182 IS - 5 ER - TY - JOUR T1 - Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations. JF - Cell Y1 - 2020 A1 - Chen, Ming-Huei A1 - Raffield, Laura M A1 - Mousas, Abdou A1 - Sakaue, Saori A1 - Huffman, Jennifer E A1 - Moscati, Arden A1 - Trivedi, Bhavi A1 - Jiang, Tao A1 - Akbari, Parsa A1 - Vuckovic, Dragana A1 - Bao, Erik L A1 - Zhong, Xue A1 - Manansala, Regina A1 - Laplante, Véronique A1 - Chen, Minhui A1 - Lo, Ken Sin A1 - Qian, Huijun A1 - Lareau, Caleb A A1 - Beaudoin, Mélissa A1 - Hunt, Karen A A1 - Akiyama, Masato A1 - Bartz, Traci M A1 - Ben-Shlomo, Yoav A1 - Beswick, Andrew A1 - Bork-Jensen, Jette A1 - Bottinger, Erwin P A1 - Brody, Jennifer A A1 - van Rooij, Frank J A A1 - Chitrala, Kumaraswamynaidu A1 - Cho, Kelly A1 - Choquet, Helene A1 - Correa, Adolfo A1 - Danesh, John A1 - Di Angelantonio, Emanuele A1 - Dimou, Niki A1 - Ding, Jingzhong A1 - Elliott, Paul A1 - Esko, Tõnu A1 - Evans, Michele K A1 - Floyd, James S A1 - Broer, Linda A1 - Grarup, Niels A1 - Guo, Michael H A1 - Greinacher, Andreas A1 - Haessler, Jeff A1 - Hansen, Torben A1 - Howson, Joanna M M A1 - Huang, Qin Qin A1 - Huang, Wei A1 - Jorgenson, Eric A1 - Kacprowski, Tim A1 - Kähönen, Mika A1 - Kamatani, Yoichiro A1 - Kanai, Masahiro A1 - Karthikeyan, Savita A1 - Koskeridis, Fotis A1 - Lange, Leslie A A1 - Lehtimäki, Terho A1 - Lerch, Markus M A1 - Linneberg, Allan A1 - Liu, Yongmei A1 - Lyytikäinen, Leo-Pekka A1 - Manichaikul, Ani A1 - Martin, Hilary C A1 - Matsuda, Koichi A1 - Mohlke, Karen L A1 - Mononen, Nina A1 - Murakami, Yoshinori A1 - Nadkarni, Girish N A1 - Nauck, Matthias A1 - Nikus, Kjell A1 - Ouwehand, Willem H A1 - Pankratz, Nathan A1 - Pedersen, Oluf A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Roberts, David J A1 - Rich, Stephen S A1 - Rodriguez, Benjamin A T A1 - Rosen, Jonathan D A1 - Rotter, Jerome I A1 - Schubert, Petra A1 - Spracklen, Cassandra N A1 - Surendran, Praveen A1 - Tang, Hua A1 - Tardif, Jean-Claude A1 - Trembath, Richard C A1 - Ghanbari, Mohsen A1 - Völker, Uwe A1 - Völzke, Henry A1 - Watkins, Nicholas A A1 - Zonderman, Alan B A1 - Wilson, Peter W F A1 - Li, Yun A1 - Butterworth, Adam S A1 - Gauchat, Jean-François A1 - Chiang, Charleston W K A1 - Li, Bingshan A1 - Loos, Ruth J F A1 - Astle, William J A1 - Evangelou, Evangelos A1 - van Heel, David A A1 - Sankaran, Vijay G A1 - Okada, Yukinori A1 - Soranzo, Nicole A1 - Johnson, Andrew D A1 - Reiner, Alexander P A1 - Auer, Paul L A1 - Lettre, Guillaume AB -

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

VL - 182 IS - 5 ER - TY - JOUR T1 - Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. JF - Nat Commun Y1 - 2021 A1 - Tin, Adrienne A1 - Schlosser, Pascal A1 - Matias-Garcia, Pamela R A1 - Thio, Chris H L A1 - Joehanes, Roby A1 - Liu, Hongbo A1 - Yu, Zhi A1 - Weihs, Antoine A1 - Hoppmann, Anselm A1 - Grundner-Culemann, Franziska A1 - Min, Josine L A1 - Kuhns, Victoria L Halperin A1 - Adeyemo, Adebowale A A1 - Agyemang, Charles A1 - Arnlöv, Johan A1 - Aziz, Nasir A A1 - Baccarelli, Andrea A1 - Bochud, Murielle A1 - Brenner, Hermann A1 - Bressler, Jan A1 - Breteler, Monique M B A1 - Carmeli, Cristian A1 - Chaker, Layal A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Correa, Adolfo A1 - Cox, Simon R A1 - Delgado, Graciela E A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Endlich, Karlhans A1 - Floyd, James S A1 - Fraszczyk, Eliza A1 - Gao, Xu A1 - Gào, Xīn A1 - Gelber, Allan C A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Gieger, Christian A1 - Greenland, Philip A1 - Grove, Megan L A1 - Harris, Sarah E A1 - Hemani, Gibran A1 - Henneman, Peter A1 - Herder, Christian A1 - Horvath, Steve A1 - Hou, Lifang A1 - Hurme, Mikko A A1 - Hwang, Shih-Jen A1 - Kardia, Sharon L R A1 - Kasela, Silva A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Kronenberg, Florian A1 - Kuhnel, Brigitte A1 - Ladd-Acosta, Christine A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Liu, Dan A1 - Lloyd-Jones, Donald M A1 - Lorkowski, Stefan A1 - Lu, Ake T A1 - Marioni, Riccardo E A1 - März, Winfried A1 - McCartney, Daniel L A1 - Meeks, Karlijn A C A1 - Milani, Lili A1 - Mishra, Pashupati P A1 - Nauck, Matthias A1 - Nowak, Christoph A1 - Peters, Annette A1 - Prokisch, Holger A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Ratliff, Scott M A1 - Reiner, Alex P A1 - Schöttker, Ben A1 - Schwartz, Joel A1 - Sedaghat, Sanaz A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stocker, Hannah R A1 - Stringhini, Silvia A1 - Sundström, Johan A1 - Swenson, Brenton R A1 - van Meurs, Joyce B J A1 - van Vliet-Ostaptchouk, Jana V A1 - Venema, Andrea A1 - Völker, Uwe A1 - Winkelmann, Juliane A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Wei A1 - Zheng, Yinan A1 - Loh, Marie A1 - Snieder, Harold A1 - Waldenberger, Melanie A1 - Levy, Daniel A1 - Akilesh, Shreeram A1 - Woodward, Owen M A1 - Susztak, Katalin A1 - Teumer, Alexander A1 - Köttgen, Anna KW - Amino Acid Transport System y+ KW - Cohort Studies KW - CpG Islands KW - DNA Methylation KW - Epigenome KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Transport Proteins, Facilitative KW - Gout KW - Humans KW - Male KW - Uric Acid AB -

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

VL - 12 IS - 1 ER - TY - JOUR T1 - Meta-analyses identify DNA methylation associated with kidney function and damage. JF - Nat Commun Y1 - 2021 A1 - Schlosser, Pascal A1 - Tin, Adrienne A1 - Matias-Garcia, Pamela R A1 - Thio, Chris H L A1 - Joehanes, Roby A1 - Liu, Hongbo A1 - Weihs, Antoine A1 - Yu, Zhi A1 - Hoppmann, Anselm A1 - Grundner-Culemann, Franziska A1 - Min, Josine L A1 - Adeyemo, Adebowale A A1 - Agyemang, Charles A1 - Arnlöv, Johan A1 - Aziz, Nasir A A1 - Baccarelli, Andrea A1 - Bochud, Murielle A1 - Brenner, Hermann A1 - Breteler, Monique M B A1 - Carmeli, Cristian A1 - Chaker, Layal A1 - Chambers, John C A1 - Cole, Shelley A A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Correa, Adolfo A1 - Cox, Simon R A1 - de Klein, Niek A1 - Delgado, Graciela E A1 - Domingo-Relloso, Arce A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Endlich, Karlhans A1 - Evans, Kathryn L A1 - Floyd, James S A1 - Fornage, Myriam A1 - Franke, Lude A1 - Fraszczyk, Eliza A1 - Gao, Xu A1 - Gào, Xīn A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Gieger, Christian A1 - Greenland, Philip A1 - Grove, Megan L A1 - Harris, Sarah E A1 - Hemani, Gibran A1 - Henneman, Peter A1 - Herder, Christian A1 - Horvath, Steve A1 - Hou, Lifang A1 - Hurme, Mikko A A1 - Hwang, Shih-Jen A1 - Jarvelin, Marjo-Riitta A1 - Kardia, Sharon L R A1 - Kasela, Silva A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Kramer, Holly A1 - Kronenberg, Florian A1 - Kuhnel, Brigitte A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Liu, Dan A1 - Liu, Yongmei A1 - Lloyd-Jones, Donald M A1 - Lohman, Kurt A1 - Lorkowski, Stefan A1 - Lu, Ake T A1 - Marioni, Riccardo E A1 - März, Winfried A1 - McCartney, Daniel L A1 - Meeks, Karlijn A C A1 - Milani, Lili A1 - Mishra, Pashupati P A1 - Nauck, Matthias A1 - Navas-Acien, Ana A1 - Nowak, Christoph A1 - Peters, Annette A1 - Prokisch, Holger A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Ratliff, Scott M A1 - Reiner, Alex P A1 - Rosas, Sylvia E A1 - Schöttker, Ben A1 - Schwartz, Joel A1 - Sedaghat, Sanaz A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stocker, Hannah R A1 - Stringhini, Silvia A1 - Sundström, Johan A1 - Swenson, Brenton R A1 - Tellez-Plaza, Maria A1 - van Meurs, Joyce B J A1 - van Vliet-Ostaptchouk, Jana V A1 - Venema, Andrea A1 - Verweij, Niek A1 - Walker, Rosie M A1 - Wielscher, Matthias A1 - Winkelmann, Juliane A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Wei A1 - Zheng, Yinan A1 - Loh, Marie A1 - Snieder, Harold A1 - Levy, Daniel A1 - Waldenberger, Melanie A1 - Susztak, Katalin A1 - Köttgen, Anna A1 - Teumer, Alexander KW - Adult KW - Aged KW - CpG Islands KW - DNA Methylation KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Interferon Regulatory Factors KW - Kidney KW - Kidney Function Tests KW - LIM Domain Proteins KW - Male KW - Membrane Proteins KW - Middle Aged KW - Renal Insufficiency, Chronic KW - Transcription Factors AB -

Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1, PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1, LDB2, CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.

VL - 12 IS - 1 ER - TY - JOUR T1 - Association of immune cell subsets with incident heart failure in two population-based cohorts. JF - ESC Heart Fail Y1 - 2022 A1 - Sinha, Arjun A1 - Sitlani, Colleen M A1 - Doyle, Margaret F A1 - Fohner, Alison E A1 - Bůzková, Petra A1 - Floyd, James S A1 - Huber, Sally A A1 - Olson, Nels C A1 - Njoroge, Joyce N A1 - Kizer, Jorge R A1 - Delaney, Joseph A A1 - Shah, Sanjiv S A1 - Tracy, Russell P A1 - Psaty, Bruce A1 - Feinstein, Matthew AB -

AIMS: Circulating inflammatory markers are associated with incident heart failure (HF), but prospective data on associations of immune cell subsets with incident HF are lacking. We determined the associations of immune cell subsets with incident HF as well as HF subtypes [with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)].

METHODS AND RESULTS: Peripheral blood immune cell subsets were measured in adults from the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS). Cox proportional hazard models adjusted for demographics, HF risk factors, and cytomegalovirus serostatus were used to evaluate the association of the immune cell subsets with incident HF. The average age of the MESA cohort at the time of immune cell measurements was 63.0 ± 10.4 years with 51% women, and in the CHS cohort, it was 79.6 ± 4.4 years with 62% women. In the meta-analysis of CHS and MESA, a higher proportion of CD4+ T helper (Th) 1 cells (per one standard deviation) was associated with a lower risk of incident HF [hazard ratio (HR) 0.91, (95% CI 0.83-0.99), P = 0.03]. Specifically, higher proportion of CD4+ Th1 cells was significantly associated with a lower risk of HFrEF [HR 0.73, (95% CI 0.62-0.85), <0.001] after correction for multiple testing. No association was observed with HFpEF. No other cell subsets were associated with incident HF.

CONCLUSIONS: We observed that higher proportions of CD4+ Th1 cells were associated with a lower risk of incident HFrEF in two distinct population-based cohorts, with similar effect sizes in both cohorts demonstrating replicability. Although unexpected, the consistency of this finding across cohorts merits further investigation.

ER - TY - JOUR T1 - Immune cell subpopulations as risk factors for atrial fibrillation: The Cardiovascular Health Study and Multi-Ethnic Study of Atherosclerosis. JF - Heart Rhythm Y1 - 2022 A1 - Floyd, James S A1 - Sitlani, Colleen M A1 - Doyle, Margaret F A1 - Feinstein, Matthew J A1 - Olson, Nels C A1 - Heckbert, Susan R A1 - Huber, Sally A A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Delaney, Joseph A C ER - TY - JOUR T1 - Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation. JF - Nat Genet Y1 - 2022 A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Zhang, Weihua A1 - Ng, Maggie C Y A1 - Petty, Lauren E A1 - Kitajima, Hidetoshi A1 - Yu, Grace Z A1 - Rüeger, Sina A1 - Speidel, Leo A1 - Kim, Young Jin A1 - Horikoshi, Momoko A1 - Mercader, Josep M A1 - Taliun, Daniel A1 - Moon, Sanghoon A1 - Kwak, Soo-Heon A1 - Robertson, Neil R A1 - Rayner, Nigel W A1 - Loh, Marie A1 - Kim, Bong-Jo A1 - Chiou, Joshua A1 - Miguel-Escalada, Irene A1 - Della Briotta Parolo, Pietro A1 - Lin, Kuang A1 - Bragg, Fiona A1 - Preuss, Michael H A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Guo, Xiuqing A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Scott, Robert A A1 - Lee, Jung-Jin A1 - Huerta-Chagoya, Alicia A1 - Graff, Mariaelisa A1 - Chai, Jin-Fang A1 - Parra, Esteban J A1 - Yao, Jie A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Steinthorsdottir, Valgerdur A1 - Cook, James P A1 - Kals, Mart A1 - Grarup, Niels A1 - Schmidt, Ellen M A1 - Pan, Ian A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Ahmad, Meraj A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Lecoeur, Cécile A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Jensen, Richard A A1 - Tajuddin, Salman A1 - Kabagambe, Edmond K A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Flanagan, Jack A1 - Abaitua, Fernando A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Akiyama, Masato A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bian, Zheng A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Brody, Jennifer A A1 - Brummett, Chad M A1 - Buchanan, Thomas A A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Das, Swapan K A1 - de Silva, H Janaka A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Fuchsberger, Christian A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Goodarzi, Mark O A1 - Gordon-Larsen, Penny A1 - Gorkin, David A1 - Gross, Myron A1 - Guo, Yu A1 - Hackinger, Sophie A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Kamatani, Yoichiro A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kohara, Katsuhiko A1 - Kriebel, Jennifer A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Ligthart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lyssenko, Valeriya A1 - Mamakou, Vasiliki A1 - Mani, K Radha A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Morris, Andrew D A1 - Nadkarni, Girish N A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Nongmaithem, Suraj S A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Preissl, Sebastian A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Kathryn A1 - Sabanayagam, Charumathi A1 - Sander, Maike A1 - Sandow, Kevin A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Schurmann, Claudia A1 - Shahriar, Mohammad A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shriner, Daniel A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Suzuki, Ken A1 - Takahashi, Atsushi A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorleifsson, Gudmar A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Torres, Jason M A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Vujkovic, Marijana A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Whitsel, Eric A A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamauchi, Toshimasa A1 - Yengo, Loic A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zhang, Liang A1 - Zheng, Wei A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Hanis, Craig L A1 - Peyser, Patricia A A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Zeggini, Eleftheria A1 - Yokota, Mitsuhiro A1 - Rich, Stephen S A1 - Kooperberg, Charles A1 - Pankow, James S A1 - Engert, James C A1 - Chen, Yii-Der Ida A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Kardia, Sharon L R A1 - Wu, Jer-Yuarn A1 - Hayes, M Geoffrey A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Groop, Leif A1 - Mook-Kanamori, Dennis O A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Bottinger, Erwin P A1 - Dehghan, Abbas A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Palmer, Colin N A A1 - Liu, Simin A1 - Abecasis, Goncalo A1 - Kooner, Jaspal S A1 - Loos, Ruth J F A1 - North, Kari E A1 - Haiman, Christopher A A1 - Florez, Jose C A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Mägi, Reedik A1 - Langenberg, Claudia A1 - Wareham, Nicholas J A1 - Maeda, Shiro A1 - Kadowaki, Takashi A1 - Lee, Juyoung A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Myers, Simon R A1 - Ferrer, Jorge A1 - Gaulton, Kyle J A1 - Meigs, James B A1 - Mohlke, Karen L A1 - Gloyn, Anna L A1 - Bowden, Donald W A1 - Below, Jennifer E A1 - Chambers, John C A1 - Sim, Xueling A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - McCarthy, Mark I A1 - Morris, Andrew P KW - Diabetes Mellitus, Type 2 KW - Ethnicity KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.

VL - 54 IS - 5 ER - TY - JOUR T1 - Proteomics and Population Biology in the Cardiovascular Health Study (CHS): design of a study with mentored access and active data sharing. JF - Eur J Epidemiol Y1 - 2022 A1 - Austin, Thomas R A1 - McHugh, Caitlin P A1 - Brody, Jennifer A A1 - Bis, Joshua C A1 - Sitlani, Colleen M A1 - Bartz, Traci M A1 - Biggs, Mary L A1 - Bansal, Nisha A1 - Bůzková, Petra A1 - Carr, Steven A A1 - deFilippi, Christopher R A1 - Elkind, Mitchell S V A1 - Fink, Howard A A1 - Floyd, James S A1 - Fohner, Alison E A1 - Gerszten, Robert E A1 - Heckbert, Susan R A1 - Katz, Daniel H A1 - Kizer, Jorge R A1 - Lemaitre, Rozenn N A1 - Longstreth, W T A1 - McKnight, Barbara A1 - Mei, Hao A1 - Mukamal, Kenneth J A1 - Newman, Anne B A1 - Ngo, Debby A1 - Odden, Michelle C A1 - Vasan, Ramachandran S A1 - Shojaie, Ali A1 - Simon, Noah A1 - Smith, George Davey A1 - Davies, Neil M A1 - Siscovick, David S A1 - Sotoodehnia, Nona A1 - Tracy, Russell P A1 - Wiggins, Kerri L A1 - Zheng, Jie A1 - Psaty, Bruce M AB -

BACKGROUND: In the last decade, genomic studies have identified and replicated thousands of genetic associations with measures of health and disease and contributed to the understanding of the etiology of a variety of health conditions. Proteins are key biomarkers in clinical medicine and often drug-therapy targets. Like genomics, proteomics can advance our understanding of biology.

METHODS AND RESULTS: In the setting of the Cardiovascular Health Study (CHS), a cohort study of older adults, an aptamer-based method that has high sensitivity for low-abundance proteins was used to assay 4979 proteins in frozen, stored plasma from 3188 participants (61% women, mean age 74 years). CHS provides active support, including central analysis, for seven phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 early or mid-career scientists. In this setting of mentored access, the proteomic data and analytic methods are widely shared with the WGs and investigators so that they may evaluate associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses. We describe the design of CHS, the CHS Proteomics Study, characteristics of participants, quality control measures, and structural characteristics of the data provided to CHS WGs. We additionally highlight plans for validation and replication of novel proteomic associations.

CONCLUSION: The CHS Proteomics Study offers an opportunity for collaborative data sharing to improve our understanding of the etiology of a variety of health conditions in older adults.

ER - TY - JOUR T1 - Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program. JF - Commun Biol Y1 - 2022 A1 - DiCorpo, Daniel A1 - Gaynor, Sheila M A1 - Russell, Emily M A1 - Westerman, Kenneth E A1 - Raffield, Laura M A1 - Majarian, Timothy D A1 - Wu, Peitao A1 - Sarnowski, Chloe A1 - Highland, Heather M A1 - Jackson, Anne A1 - Hasbani, Natalie R A1 - de Vries, Paul S A1 - Brody, Jennifer A A1 - Hidalgo, Bertha A1 - Guo, Xiuqing A1 - Perry, James A A1 - O'Connell, Jeffrey R A1 - Lent, Samantha A1 - Montasser, May E A1 - Cade, Brian E A1 - Jain, Deepti A1 - Wang, Heming A1 - D'Oliveira Albanus, Ricardo A1 - Varshney, Arushi A1 - Yanek, Lisa R A1 - Lange, Leslie A1 - Palmer, Nicholette D A1 - Almeida, Marcio A1 - Peralta, Juan M A1 - Aslibekyan, Stella A1 - Baldridge, Abigail S A1 - Bertoni, Alain G A1 - Bielak, Lawrence F A1 - Chen, Chung-Shiuan A1 - Chen, Yii-Der Ida A1 - Choi, Won Jung A1 - Goodarzi, Mark O A1 - Floyd, James S A1 - Irvin, Marguerite R A1 - Kalyani, Rita R A1 - Kelly, Tanika N A1 - Lee, Seonwook A1 - Liu, Ching-Ti A1 - Loesch, Douglas A1 - Manson, JoAnn E A1 - Minster, Ryan L A1 - Naseri, Take A1 - Pankow, James S A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Reupena, Muagututi'a Sefuiva A1 - Selvin, Elizabeth A1 - Smith, Jennifer A A1 - Weeks, Daniel E A1 - Xu, Huichun A1 - Yao, Jie A1 - Zhao, Wei A1 - Parker, Stephen A1 - Alonso, Alvaro A1 - Arnett, Donna K A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Correa, Adolfo A1 - Cupples, L Adrienne A1 - Curran, Joanne E A1 - Duggirala, Ravindranath A1 - He, Jiang A1 - Heckbert, Susan R A1 - Kardia, Sharon L R A1 - Kim, Ryan W A1 - Kooperberg, Charles A1 - Liu, Simin A1 - Mathias, Rasika A A1 - McGarvey, Stephen T A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Peyser, Patricia A A1 - Psaty, Bruce M A1 - Redline, Susan A1 - Shuldiner, Alan R A1 - Taylor, Kent D A1 - Vasan, Ramachandran S A1 - Viaud-Martinez, Karine A A1 - Florez, Jose C A1 - Wilson, James G A1 - Sladek, Robert A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Lin, Xihong A1 - Dupuis, Josée A1 - Meigs, James B A1 - Wessel, Jennifer A1 - Manning, Alisa K KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Glucose KW - Humans KW - Insulin KW - National Heart, Lung, and Blood Institute (U.S.) KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Precision Medicine KW - Receptors, Immunologic KW - United States AB -

The genetic determinants of fasting glucose (FG) and fasting insulin (FI) have been studied mostly through genome arrays, resulting in over 100 associated variants. We extended this work with high-coverage whole genome sequencing analyses from fifteen cohorts in NHLBI's Trans-Omics for Precision Medicine (TOPMed) program. Over 23,000 non-diabetic individuals from five race-ethnicities/populations (African, Asian, European, Hispanic and Samoan) were included. Eight variants were significantly associated with FG or FI across previously identified regions MTNR1B, G6PC2, GCK, GCKR and FOXA2. We additionally characterize suggestive associations with FG or FI near previously identified SLC30A8, TCF7L2, and ADCY5 regions as well as APOB, PTPRT, and ROBO1. Functional annotation resources including the Diabetes Epigenome Atlas were compiled for each signal (chromatin states, annotation principal components, and others) to elucidate variant-to-function hypotheses. We provide a catalog of nucleotide-resolution genomic variation spanning intergenic and intronic regions creating a foundation for future sequencing-based investigations of glycemic traits.

VL - 5 IS - 1 ER - TY - JOUR T1 - Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program. JF - Nat Commun Y1 - 2022 A1 - Wheeler, Marsha M A1 - Stilp, Adrienne M A1 - Rao, Shuquan A1 - Halldorsson, Bjarni V A1 - Beyter, Doruk A1 - Wen, Jia A1 - Mihkaylova, Anna V A1 - McHugh, Caitlin P A1 - Lane, John A1 - Jiang, Min-Zhi A1 - Raffield, Laura M A1 - Jun, Goo A1 - Sedlazeck, Fritz J A1 - Metcalf, Ginger A1 - Yao, Yao A1 - Bis, Joshua B A1 - Chami, Nathalie A1 - de Vries, Paul S A1 - Desai, Pinkal A1 - Floyd, James S A1 - Gao, Yan A1 - Kammers, Kai A1 - Kim, Wonji A1 - Moon, Jee-Young A1 - Ratan, Aakrosh A1 - Yanek, Lisa R A1 - Almasy, Laura A1 - Becker, Lewis C A1 - Blangero, John A1 - Cho, Michael H A1 - Curran, Joanne E A1 - Fornage, Myriam A1 - Kaplan, Robert C A1 - Lewis, Joshua P A1 - Loos, Ruth J F A1 - Mitchell, Braxton D A1 - Morrison, Alanna C A1 - Preuss, Michael A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Tang, Hua A1 - Tracy, Russell P A1 - Boerwinkle, Eric A1 - Abecasis, Goncalo R A1 - Blackwell, Thomas W A1 - Smith, Albert V A1 - Johnson, Andrew D A1 - Mathias, Rasika A A1 - Nickerson, Deborah A A1 - Conomos, Matthew P A1 - Li, Yun A1 - Þorsteinsdottir, Unnur A1 - Magnússon, Magnús K A1 - Stefansson, Kari A1 - Pankratz, Nathan D A1 - Bauer, Daniel E A1 - Auer, Paul L A1 - Reiner, Alex P KW - Blood Cells KW - Genome-Wide Association Study KW - Humans KW - Whole Genome Sequencing AB -

Genome-wide association studies have identified thousands of single nucleotide variants and small indels that contribute to variation in hematologic traits. While structural variants are known to cause rare blood or hematopoietic disorders, the genome-wide contribution of structural variants to quantitative blood cell trait variation is unknown. Here we utilized whole genome sequencing data in ancestrally diverse participants of the NHLBI Trans Omics for Precision Medicine program (N = 50,675) to detect structural variants associated with hematologic traits. Using single variant tests, we assessed the association of common and rare structural variants with red cell-, white cell-, and platelet-related quantitative traits and observed 21 independent signals (12 common and 9 rare) reaching genome-wide significance. The majority of these associations (N = 18) replicated in independent datasets. In genome-editing experiments, we provide evidence that a deletion associated with lower monocyte counts leads to disruption of an S1PR3 monocyte enhancer and decreased S1PR3 expression.

VL - 13 IS - 1 ER - TY - JOUR T1 - Association of Severe Hypercholesterolemia and Familial Hypercholesterolemia Genotype With Risk of Coronary Heart Disease. JF - Circulation Y1 - 2023 A1 - Zhang, Yiyi A1 - Dron, Jacqueline S A1 - Bellows, Brandon K A1 - Khera, Amit V A1 - Liu, Junxiu A1 - Balte, Pallavi P A1 - Oelsner, Elizabeth C A1 - Amr, Sami Samir A1 - Lebo, Matthew S A1 - Nagy, Anna A1 - Peloso, Gina M A1 - Natarajan, Pradeep A1 - Rotter, Jerome I A1 - Willer, Cristen A1 - Boerwinkle, Eric A1 - Ballantyne, Christie M A1 - Lutsey, Pamela L A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Floyd, James S A1 - Vasan, Ramachandran S A1 - Heard-Costa, Nancy L A1 - Carson, April P A1 - Hall, Michael E A1 - Rich, Stephen S A1 - Guo, Xiuqing A1 - Kazi, Dhruv S A1 - de Ferranti, Sarah D A1 - Moran, Andrew E KW - Coronary Disease KW - Genotype KW - Humans KW - Hypercholesterolemia KW - Hyperlipoproteinemia Type II VL - 147 IS - 20 ER - TY - JOUR T1 - Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci. JF - Front Genet Y1 - 2023 A1 - de Las Fuentes, Lisa A1 - Schwander, Karen L A1 - Brown, Michael R A1 - Bentley, Amy R A1 - Winkler, Thomas W A1 - Sung, Yun Ju A1 - Munroe, Patricia B A1 - Miller, Clint L A1 - Aschard, Hugo A1 - Aslibekyan, Stella A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Chai, Jin Fang A1 - Cheng, Ching-Yu A1 - Dorajoo, Rajkumar A1 - Feitosa, Mary F A1 - Guo, Xiuqing A1 - Hartwig, Fernando P A1 - Horimoto, Andrea A1 - Kolcic, Ivana A1 - Lim, Elise A1 - Liu, Yongmei A1 - Manning, Alisa K A1 - Marten, Jonathan A1 - Musani, Solomon K A1 - Noordam, Raymond A1 - Padmanabhan, Sandosh A1 - Rankinen, Tuomo A1 - Richard, Melissa A A1 - Ridker, Paul M A1 - Smith, Albert V A1 - Vojinovic, Dina A1 - Zonderman, Alan B A1 - Alver, Maris A1 - Boissel, Mathilde A1 - Christensen, Kaare A1 - Freedman, Barry I A1 - Gao, Chuan A1 - Giulianini, Franco A1 - Harris, Sarah E A1 - He, Meian A1 - Hsu, Fang-Chi A1 - Kuhnel, Brigitte A1 - Laguzzi, Federica A1 - Li, Xiaoyin A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Poveda, Alaitz A1 - Rauramaa, Rainer A1 - Riaz, Muhammad A1 - Robino, Antonietta A1 - Sofer, Tamar A1 - Takeuchi, Fumihiko A1 - Tayo, Bamidele O A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Ware, Erin B A1 - Weiss, Stefan A1 - Wen, Wanqing A1 - Yanek, Lisa R A1 - Zhan, Yiqiang A1 - Amin, Najaf A1 - Arking, Dan E A1 - Ballantyne, Christie A1 - Boerwinkle, Eric A1 - Brody, Jennifer A A1 - Broeckel, Ulrich A1 - Campbell, Archie A1 - Canouil, Mickaël A1 - Chai, Xiaoran A1 - Chen, Yii-Der Ida A1 - Chen, Xu A1 - Chitrala, Kumaraswamy Naidu A1 - Concas, Maria Pina A1 - de Faire, Ulf A1 - de Mutsert, Renée A1 - de Silva, H Janaka A1 - de Vries, Paul S A1 - Do, Ahn A1 - Faul, Jessica D A1 - Fisher, Virginia A1 - Floyd, James S A1 - Forrester, Terrence A1 - Friedlander, Yechiel A1 - Girotto, Giorgia A1 - Gu, C Charles A1 - Hallmans, Göran A1 - Heikkinen, Sami A1 - Heng, Chew-Kiat A1 - Homuth, Georg A1 - Hunt, Steven A1 - Ikram, M Arfan A1 - Jacobs, David R A1 - Kavousi, Maryam A1 - Khor, Chiea Chuen A1 - Kilpeläinen, Tuomas O A1 - Koh, Woon-Puay A1 - Komulainen, Pirjo A1 - Langefeld, Carl D A1 - Liang, Jingjing A1 - Liu, Kiang A1 - Liu, Jianjun A1 - Lohman, Kurt A1 - Mägi, Reedik A1 - Manichaikul, Ani W A1 - McKenzie, Colin A A1 - Meitinger, Thomas A1 - Milaneschi, Yuri A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Pereira, Alexandre C A1 - Perls, Thomas A1 - Peters, Annette A1 - Polasek, Ozren A1 - Raitakari, Olli T A1 - Rice, Kenneth A1 - Rice, Treva K A1 - Rich, Stephen S A1 - Sabanayagam, Charumathi A1 - Schreiner, Pamela J A1 - Shu, Xiao-Ou A1 - Sidney, Stephen A1 - Sims, Mario A1 - Smith, Jennifer A A1 - Starr, John M A1 - Strauch, Konstantin A1 - Tai, E Shyong A1 - Taylor, Kent D A1 - Tsai, Michael Y A1 - Uitterlinden, André G A1 - van Heemst, Diana A1 - Waldenberger, Melanie A1 - Wang, Ya-Xing A1 - Wei, Wen-Bin A1 - Wilson, Gregory A1 - Xuan, Deng A1 - Yao, Jie A1 - Yu, Caizheng A1 - Yuan, Jian-Min A1 - Zhao, Wei A1 - Becker, Diane M A1 - Bonnefond, Amélie A1 - Bowden, Donald W A1 - Cooper, Richard S A1 - Deary, Ian J A1 - Divers, Jasmin A1 - Esko, Tõnu A1 - Franks, Paul W A1 - Froguel, Philippe A1 - Gieger, Christian A1 - Jonas, Jost B A1 - Kato, Norihiro A1 - Lakka, Timo A A1 - Leander, Karin A1 - Lehtimäki, Terho A1 - Magnusson, Patrik K E A1 - North, Kari E A1 - Ntalla, Ioanna A1 - Penninx, Brenda A1 - Samani, Nilesh J A1 - Snieder, Harold A1 - Spedicati, Beatrice A1 - van der Harst, Pim A1 - Völzke, Henry A1 - Wagenknecht, Lynne E A1 - Weir, David R A1 - Wojczynski, Mary K A1 - Wu, Tangchun A1 - Zheng, Wei A1 - Zhu, Xiaofeng A1 - Bouchard, Claude A1 - Chasman, Daniel I A1 - Evans, Michele K A1 - Fox, Ervin R A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Horta, Bernardo L A1 - Kardia, Sharon L R A1 - Krieger, Jose Eduardo A1 - Mook-Kanamori, Dennis O A1 - Peyser, Patricia A A1 - Province, Michael M A1 - Psaty, Bruce M A1 - Rudan, Igor A1 - Sim, Xueling A1 - Smith, Blair H A1 - van Dam, Rob M A1 - van Duijn, Cornelia M A1 - Wong, Tien Yin A1 - Arnett, Donna K A1 - Rao, Dabeeru C A1 - Gauderman, James A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Fornage, Myriam AB -

Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant ( < 5 × 10) and suggestive ( < 1 × 10) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (), brain (), and liver () biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

VL - 14 ER - TY - JOUR T1 - Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications. JF - medRxiv Y1 - 2023 A1 - Suzuki, Ken A1 - Hatzikotoulas, Konstantinos A1 - Southam, Lorraine A1 - Taylor, Henry J A1 - Yin, Xianyong A1 - Lorenz, Kim M A1 - Mandla, Ravi A1 - Huerta-Chagoya, Alicia A1 - Rayner, Nigel W A1 - Bocher, Ozvan A1 - Ana Luiza de, S V Arruda A1 - Sonehara, Kyuto A1 - Namba, Shinichi A1 - Lee, Simon S K A1 - Preuss, Michael H A1 - Petty, Lauren E A1 - Schroeder, Philip A1 - Vanderwerff, Brett A1 - Kals, Mart A1 - Bragg, Fiona A1 - Lin, Kuang A1 - Guo, Xiuqing A1 - Zhang, Weihua A1 - Yao, Jie A1 - Kim, Young Jin A1 - Graff, Mariaelisa A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Moon, Sanghoon A1 - Scott, Robert A A1 - Cook, James P A1 - Lee, Jung-Jin A1 - Pan, Ian A1 - Taliun, Daniel A1 - Parra, Esteban J A1 - Chai, Jin-Fang A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Thorleifsson, Gudmar A1 - Grarup, Niels A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Kwak, Soo-Heon A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Nongmaithem, Suraj S A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Brody, Jennifer A A1 - Kabagambe, Edmond A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Alaine Broadaway, K A1 - Williamson, Alice A1 - Kamali, Zoha A1 - Cui, Jinrui A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Ahluwalia, Tarunveer S A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Buchanan, Thomas A A1 - Burant, Charles F A1 - Butterworth, Adam S A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Danesh, John A1 - Das, Swapan K A1 - Janaka de Silva, H A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Gordon-Larsen, Penny A1 - Gross, Myron A1 - Guare, Lindsay A A1 - Hackinger, Sophie A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Horikoshi, Momoko A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Torben A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Kyung Min A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Lithgart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lynch, Julie A A1 - Lyssenko, Valeriya A1 - Maeda, Shiro A1 - Mamakou, Vasiliki A1 - Mansuri, Sohail Rafik A1 - Matsuda, Koichi A1 - Meitinger, Thomas A1 - Metspalu, Andres A1 - Mo, Huan A1 - Morris, Andrew D A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Patil, Snehal A1 - Pei, Pei A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Polikowsky, Hannah G A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Katheryn A1 - Sabanayagam, Charumathi A1 - Sandow, Kevin A1 - Sankareswaran, Alagu A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Shahriar, Mohammad A1 - Shen, Botong A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shojima, Nobuhiro A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Steinthorsdottir, Valgerdur A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Tran, Tam C A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamamoto, Kenichi A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zawistowski, Matthew A1 - Zhang, Liang A1 - Zheng, Wei A1 - Project, Biobank Japan A1 - BioBank, Penn Medicine A1 - Center, Regeneron Genetics A1 - Consortium, eMERGE A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Fornage, Myriam A1 - Hanis, Craig L A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Yokota, Mitsuhiro A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - Pankow, James S A1 - Engert, James C A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Wu, Jer-Yuarn A1 - Geoffrey Hayes, M A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Mook-Kanamori, Dennis O A1 - Tuomi, Tiinamaija A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - Chen, Yii-Der Ida A1 - Rich, Stephen S A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Ghanbari, Mohsen A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Bowden, Donald W A1 - Palmer, Colin N A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Liu, Simin A1 - North, Kari E A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Wareham, Nicholas J A1 - Lee, Juyoung A1 - Kim, Bong-Jo A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Goodarzi, Mark O A1 - Mohlke, Karen L A1 - Langenberg, Claudia A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - Florez, Jose C A1 - Rader, Daniel J A1 - Ritchie, Marylyn D A1 - Zöllner, Sebastian A1 - Mägi, Reedik A1 - Denny, Joshua C A1 - Yamauchi, Toshimasa A1 - Kadowaki, Takashi A1 - Chambers, John C A1 - Ng, Maggie C Y A1 - Sim, Xueling A1 - Below, Jennifer E A1 - Tsao, Philip S A1 - Chang, Kyong-Mi A1 - McCarthy, Mark I A1 - Meigs, James B A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Mercader, Josep M A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - Vujkovic, Marijana A1 - Voight, Benjamin F A1 - Morris, Andrew P A1 - Zeggini, Eleftheria AB -

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases. We identify 1,289 independent association signals at genome-wide significance (P<5×10 ) that map to 611 loci, of which 145 loci are previously unreported. We define eight non-overlapping clusters of T2D signals characterised by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial, and enteroendocrine cells. We build cluster-specific partitioned genetic risk scores (GRS) in an additional 137,559 individuals of diverse ancestry, including 10,159 T2D cases, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned GRS are more strongly associated with coronary artery disease and end-stage diabetic nephropathy than an overall T2D GRS across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings demonstrate the value of integrating multi-ancestry GWAS with single-cell epigenomics to disentangle the aetiological heterogeneity driving the development and progression of T2D, which may offer a route to optimise global access to genetically-informed diabetes care.

ER - TY - JOUR T1 - Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study. JF - Neurology Y1 - 2023 A1 - Kalani, Rizwan A1 - Bartz, Traci M A1 - Psaty, Bruce M A1 - Elkind, Mitchell S V A1 - Floyd, James S A1 - Gerszten, Robert E A1 - Shojaie, Ali A1 - Heckbert, Susan R A1 - Bis, Joshua C A1 - Austin, Thomas R A1 - Tirschwell, David L A1 - Delaney, Joseph A C A1 - Longstreth, W T AB -

BACKGROUND: Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS).

METHODS: Eligible CHS participants were free of prevalent stroke and underwent quantification of 1298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992-1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-standard deviation increase in the log-2 transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and non-cardioembolic IS as well as proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation.

RESULTS: Of 2983 eligible participants, the mean age was 74.3 (± 4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal pro-brain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23-1.53, P=2.08x10) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16-1.45, P=4.55x10) were independently associated with IS risk. These two associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident non-cardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction.

CONCLUSIONS: In a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and non-cardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.

ER - TY - JOUR T1 - A proteomic analysis of atrial fibrillation in a prospective longitudinal cohort (AGES-Reykjavik study). JF - Europace Y1 - 2023 A1 - Jonmundsson, Thorarinn A1 - Steindorsdottir, Anna E A1 - Austin, Thomas R A1 - Frick, Elisabet A A1 - Axelsson, Gisli T A1 - Launer, Lenore A1 - Psaty, Bruce M A1 - Loureiro, Joseph A1 - Orth, Anthony P A1 - Aspelund, Thor A1 - Emilsson, Valur A1 - Floyd, James S A1 - Jennings, Lori A1 - Gudnason, Vilmundur A1 - Gudmundsdottir, Valborg KW - Atrial Fibrillation KW - Biomarkers KW - Endosomal Sorting Complexes Required for Transport KW - Humans KW - Natriuretic Peptide, Brain KW - Oxidoreductases Acting on Sulfur Group Donors KW - Peptide Fragments KW - Prognosis KW - Prospective Studies KW - Proteomics KW - Risk Factors AB -

AIMS: Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4137 serum proteins and incident AF in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study.

METHODS AND RESULTS: The study included 4765 participants, of whom 1172 developed AF. Cox proportional hazards regression models were fitted for 4137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent area under the receiver operating characteristic curve (AUC)-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models. The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83%) were novel and 29 (38%) were replicated in CHS. The signature included both N-terminal prohormone of brain natriuretic peptide (NT-proBNP)-dependent (e.g. CHST15, ATP1B1, and SVEP1) and independent components (e.g. ASPN, AKR1B, and LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, and SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all time points.

CONCLUSION: The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment.

VL - 25 IS - 11 ER - TY - JOUR T1 - Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study. JF - medRxiv Y1 - 2023 A1 - Wang, Yuxuan A1 - Selvaraj, Margaret Sunitha A1 - Li, Xihao A1 - Li, Zilin A1 - Holdcraft, Jacob A A1 - Arnett, Donna K A1 - Bis, Joshua C A1 - Blangero, John A1 - Boerwinkle, Eric A1 - Bowden, Donald W A1 - Cade, Brian E A1 - Carlson, Jenna C A1 - Carson, April P A1 - Chen, Yii-Der Ida A1 - Curran, Joanne E A1 - de Vries, Paul S A1 - Dutcher, Susan K A1 - Ellinor, Patrick T A1 - Floyd, James S A1 - Fornage, Myriam A1 - Freedman, Barry I A1 - Gabriel, Stacey A1 - Germer, Soren A1 - Gibbs, Richard A A1 - Guo, Xiuqing A1 - He, Jiang A1 - Heard-Costa, Nancy A1 - Hildalgo, Bertha A1 - Hou, Lifang A1 - Irvin, Marguerite R A1 - Joehanes, Roby A1 - Kaplan, Robert C A1 - Kardia, Sharon Lr A1 - Kelly, Tanika N A1 - Kim, Ryan A1 - Kooperberg, Charles A1 - Kral, Brian G A1 - Levy, Daniel A1 - Li, Changwei A1 - Liu, Chunyu A1 - Lloyd-Jone, Don A1 - Loos, Ruth Jf A1 - Mahaney, Michael C A1 - Martin, Lisa W A1 - Mathias, Rasika A A1 - Minster, Ryan L A1 - Mitchell, Braxton D A1 - Montasser, May E A1 - Morrison, Alanna C A1 - Murabito, Joanne M A1 - Naseri, Take A1 - O'Connell, Jeffrey R A1 - Palmer, Nicholette D A1 - Preuss, Michael H A1 - Psaty, Bruce M A1 - Raffield, Laura M A1 - Rao, Dabeeru C A1 - Redline, Susan A1 - Reiner, Alexander P A1 - Rich, Stephen S A1 - Ruepena, Muagututi'a Sefuiva A1 - Sheu, Wayne H-H A1 - Smith, Jennifer A A1 - Smith, Albert A1 - Tiwari, Hemant K A1 - Tsai, Michael Y A1 - Viaud-Martinez, Karine A A1 - Wang, Zhe A1 - Yanek, Lisa R A1 - Zhao, Wei A1 - Rotter, Jerome I A1 - Lin, Xihong A1 - Natarajan, Pradeep A1 - Peloso, Gina M AB -

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.

ER - TY - JOUR T1 - A Type 1 Diabetes Polygenic Score Is Not Associated With Prevalent Type 2 Diabetes in Large Population Studies. JF - J Endocr Soc Y1 - 2023 A1 - Srinivasan, Shylaja A1 - Wu, Peitao A1 - Mercader, Josep M A1 - Udler, Miriam S A1 - Porneala, Bianca C A1 - Bartz, Traci M A1 - Floyd, James S A1 - Sitlani, Colleen A1 - Guo, Xiquing A1 - Haessler, Jeffrey A1 - Kooperberg, Charles A1 - Liu, Jun A1 - Ahmad, Shahzad A1 - van Duijn, Cornelia A1 - Liu, Ching-Ti A1 - Goodarzi, Mark O A1 - Florez, Jose C A1 - Meigs, James B A1 - Rotter, Jerome I A1 - Rich, Stephen S A1 - Dupuis, Josée A1 - Leong, Aaron AB -

CONTEXT: Both type 1 diabetes (T1D) and type 2 diabetes (T2D) have significant genetic contributions to risk and understanding their overlap can offer clinical insight.

OBJECTIVE: We examined whether a T1D polygenic score (PS) was associated with a diagnosis of T2D in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: We constructed a T1D PS using 79 known single nucleotide polymorphisms associated with T1D risk. We analyzed 13 792 T2D cases and 14 169 controls from CHARGE cohorts to determine the association between the T1D PS and T2D prevalence. We validated findings in an independent sample of 2256 T2D cases and 27 052 controls from the Mass General Brigham Biobank (MGB Biobank). As secondary analyses in 5228 T2D cases from CHARGE, we used multivariable regression models to assess the association of the T1D PS with clinical outcomes associated with T1D.

RESULTS: The T1D PS was not associated with T2D both in CHARGE ( = .15) and in the MGB Biobank ( = .87). The partitioned human leukocyte antigens only PS was associated with T2D in CHARGE (OR 1.02 per 1 SD increase in PS, 95% CI 1.01-1.03, = .006) but not in the MGB Biobank. The T1D PS was weakly associated with insulin use (OR 1.007, 95% CI 1.001-1.012, = .03) in CHARGE T2D cases but not with other outcomes.

CONCLUSION: In large biobank samples, a common variant PS for T1D was not consistently associated with prevalent T2D. However, possible heterogeneity in T2D cannot be ruled out and future studies are needed do subphenotyping.

VL - 7 IS - 11 ER - TY - JOUR T1 - Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. JF - medRxiv Y1 - 2023 A1 - Huffman, Jennifer E A1 - Nicolas, Jayna A1 - Hahn, Julie A1 - Heath, Adam S A1 - Raffield, Laura M A1 - Yanek, Lisa R A1 - Brody, Jennifer A A1 - Thibord, Florian A1 - Almasy, Laura A1 - Bartz, Traci M A1 - Bielak, Lawrence F A1 - Bowler, Russell P A1 - Carrasquilla, Germán D A1 - Chasman, Daniel I A1 - Chen, Ming-Huei A1 - Emmert, David B A1 - Ghanbari, Mohsen A1 - Haessle, Jeffery A1 - Hottenga, Jouke-Jan A1 - Kleber, Marcus E A1 - Le, Ngoc-Quynh A1 - Lee, Jiwon A1 - Lewis, Joshua P A1 - Li-Gao, Ruifang A1 - Luan, Jian'an A1 - Malmberg, Anni A1 - Mangino, Massimo A1 - Marioni, Riccardo E A1 - Martinez-Perez, Angel A1 - Pankratz, Nathan A1 - Polasek, Ozren A1 - Richmond, Anne A1 - Rodriguez, Benjamin At A1 - Rotter, Jerome I A1 - Steri, Maristella A1 - Suchon, Pierre A1 - Trompet, Stella A1 - Weiss, Stefan A1 - Zare, Marjan A1 - Auer, Paul A1 - Cho, Michael H A1 - Christofidou, Paraskevi A1 - Davies, Gail A1 - de Geus, Eco A1 - Deleuze, Jean-Francois A1 - Delgado, Graciela E A1 - Ekunwe, Lynette A1 - Faraday, Nauder A1 - Gögele, Martin A1 - Greinacher, Andreas A1 - He, Gao A1 - Howard, Tom A1 - Joshi, Peter K A1 - Kilpeläinen, Tuomas O A1 - Lahti, Jari A1 - Linneberg, Allan A1 - Naitza, Silvia A1 - Noordam, Raymond A1 - Paüls-Vergés, Ferran A1 - Rich, Stephen S A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Ryan, Kathleen A A1 - Souto, Juan Carlos A1 - van Rooij, Frank Ja A1 - Wang, Heming A1 - Zhao, Wei A1 - Becker, Lewis C A1 - Beswick, Andrew A1 - Brown, Michael R A1 - Cade, Brian E A1 - Campbell, Harry A1 - Cho, Kelly A1 - Crapo, James D A1 - Curran, Joanne E A1 - de Maat, Moniek Pm A1 - Doyle, Margaret A1 - Elliott, Paul A1 - Floyd, James S A1 - Fuchsberger, Christian A1 - Grarup, Niels A1 - Guo, Xiuqing A1 - Harris, Sarah E A1 - Hou, Lifang A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Menni, Cristina A1 - Nauck, Matthias A1 - O'Connell, Jeffrey R A1 - Orrù, Valeria A1 - Psaty, Bruce M A1 - Räikkönen, Katri A1 - Smith, Jennifer A A1 - Soria, José Manuel A1 - Stott, David J A1 - van Hylckama Vlieg, Astrid A1 - Watkins, Hugh A1 - Willemsen, Gonneke A1 - Wilson, Peter A1 - Ben-Shlomo, Yoav A1 - Blangero, John A1 - Boomsma, Dorret A1 - Cox, Simon R A1 - Dehghan, Abbas A1 - Eriksson, Johan G A1 - Fiorillo, Edoardo A1 - Fornage, Myriam A1 - Hansen, Torben A1 - Hayward, Caroline A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Kardia, Sharon Lr A1 - Lange, Leslie A A1 - März, Winfried A1 - Mathias, Rasika A A1 - Mitchell, Braxton D A1 - Mook-Kanamori, Dennis O A1 - Morange, Pierre-Emmanuel A1 - Pedersen, Oluf A1 - Pramstaller, Peter P A1 - Redline, Susan A1 - Reiner, Alexander A1 - Ridker, Paul M A1 - Silverman, Edwin K A1 - Spector, Tim D A1 - Völker, Uwe A1 - Wareham, Nick A1 - Wilson, James F A1 - Yao, Jie A1 - Trégouët, David-Alexandre A1 - Johnson, Andrew D A1 - Wolberg, Alisa S A1 - de Vries, Paul S A1 - Sabater-Lleal, Maria A1 - Morrison, Alanna C A1 - Smith, Nicholas L AB -

UNLABELLED: Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole genome sequencing (WGS) data provides better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the NHLBI's Trans-Omics for Precision Medicine (TOPMed) program (n=32,572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=131,340) imputed to the TOPMed or Haplotype Reference Consortium panel. We identified 18 loci that have not been identified in prior genetic studies of fibrinogen. Of these, four are driven by common variants of small effect with reported MAF at least 10% higher in African populations. Three ( , and signals contain predicted deleterious missense variants. Two loci, and , each harbor two conditionally distinct, non-coding variants. The gene region encoding the protein chain subunits ( ), contains 7 distinct signals, including one novel signal driven by rs28577061, a variant common (MAF=0.180) in African reference panels but extremely rare (MAF=0.008) in Europeans. Through phenome-wide association studies in the VA Million Veteran Program, we found associations between fibrinogen polygenic risk scores and thrombotic and inflammatory disease phenotypes, including an association with gout. Our findings demonstrate the utility of WGS to augment genetic discovery in diverse populations and offer new insights for putative mechanisms of fibrinogen regulation.

KEY POINTS: Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 conditionally distinct variants (20 novel).Sufficient power achieved to identify signal driven by African population variant.Links to (1) liver enzyme, blood cell and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

ER - TY - JOUR T1 - Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program. JF - Front Genet Y1 - 2023 A1 - Armstrong, Nicole D A1 - Srinivasasainagendra, Vinodh A1 - Ammous, Farah A1 - Assimes, Themistocles L A1 - Beitelshees, Amber L A1 - Brody, Jennifer A1 - Cade, Brian E A1 - Ida Chen, Yii-Der A1 - Chen, Han A1 - de Vries, Paul S A1 - Floyd, James S A1 - Franceschini, Nora A1 - Guo, Xiuqing A1 - Hellwege, Jacklyn N A1 - House, John S A1 - Hwu, Chii-Min A1 - Kardia, Sharon L R A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - McDonough, Caitrin W A1 - Montasser, May E A1 - O'Connell, Jeffrey R A1 - Shuey, Megan M A1 - Sun, Xiao A1 - Tanner, Rikki M A1 - Wang, Zhe A1 - Zhao, Wei A1 - Carson, April P A1 - Edwards, Todd L A1 - Kelly, Tanika N A1 - Kenny, Eimear E A1 - Kooperberg, Charles A1 - Loos, Ruth J F A1 - Morrison, Alanna C A1 - Motsinger-Reif, Alison A1 - Psaty, Bruce M A1 - Rao, Dabeeru C A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Irvin, Marguerite R A1 - Arnett, Donna K AB -

Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg, or four or more medications regardless of BP ( = 1,705). A normotensive control group was defined as individuals with BP < 140/90 mmHg ( = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90 mmHg ( = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). One variant in the known HTN locus, , was a top finding in the multi-ethnic analysis ( = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes and . Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.

VL - 14 ER - TY - JOUR T1 - Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol. JF - JAMA Cardiol Y1 - 2024 A1 - Zhang, Yiyi A1 - Dron, Jacqueline S A1 - Bellows, Brandon K A1 - Khera, Amit V A1 - Liu, Junxiu A1 - Balte, Pallavi P A1 - Oelsner, Elizabeth C A1 - Amr, Sami Samir A1 - Lebo, Matthew S A1 - Nagy, Anna A1 - Peloso, Gina M A1 - Natarajan, Pradeep A1 - Rotter, Jerome I A1 - Willer, Cristen A1 - Boerwinkle, Eric A1 - Ballantyne, Christie M A1 - Lutsey, Pamela L A1 - Fornage, Myriam A1 - Lloyd-Jones, Donald M A1 - Hou, Lifang A1 - Psaty, Bruce M A1 - Bis, Joshua C A1 - Floyd, James S A1 - Vasan, Ramachandran S A1 - Heard-Costa, Nancy L A1 - Carson, April P A1 - Hall, Michael E A1 - Rich, Stephen S A1 - Guo, Xiuqing A1 - Kazi, Dhruv S A1 - de Ferranti, Sarah D A1 - Moran, Andrew E AB -

IMPORTANCE: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.

OBJECTIVE: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.

DESIGN, SETTING, AND PARTICIPANTS: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023.

EXPOSURES: LDL-C, cumulative past LDL-C, FH variant status.

MAIN OUTCOMES AND MEASURES: Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults.

RESULTS: Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant.

CONCLUSIONS AND RELEVANCE: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

ER - TY - JOUR T1 - Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. JF - Nature Y1 - 2024 A1 - Suzuki, Ken A1 - Hatzikotoulas, Konstantinos A1 - Southam, Lorraine A1 - Taylor, Henry J A1 - Yin, Xianyong A1 - Lorenz, Kim M A1 - Mandla, Ravi A1 - Huerta-Chagoya, Alicia A1 - Melloni, Giorgio E M A1 - Kanoni, Stavroula A1 - Rayner, Nigel W A1 - Bocher, Ozvan A1 - Arruda, Ana Luiza A1 - Sonehara, Kyuto A1 - Namba, Shinichi A1 - Lee, Simon S K A1 - Preuss, Michael H A1 - Petty, Lauren E A1 - Schroeder, Philip A1 - Vanderwerff, Brett A1 - Kals, Mart A1 - Bragg, Fiona A1 - Lin, Kuang A1 - Guo, Xiuqing A1 - Zhang, Weihua A1 - Yao, Jie A1 - Kim, Young Jin A1 - Graff, Mariaelisa A1 - Takeuchi, Fumihiko A1 - Nano, Jana A1 - Lamri, Amel A1 - Nakatochi, Masahiro A1 - Moon, Sanghoon A1 - Scott, Robert A A1 - Cook, James P A1 - Lee, Jung-Jin A1 - Pan, Ian A1 - Taliun, Daniel A1 - Parra, Esteban J A1 - Chai, Jin-Fang A1 - Bielak, Lawrence F A1 - Tabara, Yasuharu A1 - Hai, Yang A1 - Thorleifsson, Gudmar A1 - Grarup, Niels A1 - Sofer, Tamar A1 - Wuttke, Matthias A1 - Sarnowski, Chloe A1 - Gieger, Christian A1 - Nousome, Darryl A1 - Trompet, Stella A1 - Kwak, Soo-Heon A1 - Long, Jirong A1 - Sun, Meng A1 - Tong, Lin A1 - Chen, Wei-Min A1 - Nongmaithem, Suraj S A1 - Noordam, Raymond A1 - Lim, Victor J Y A1 - Tam, Claudia H T A1 - Joo, Yoonjung Yoonie A1 - Chen, Chien-Hsiun A1 - Raffield, Laura M A1 - Prins, Bram Peter A1 - Nicolas, Aude A1 - Yanek, Lisa R A1 - Chen, Guanjie A1 - Brody, Jennifer A A1 - Kabagambe, Edmond A1 - An, Ping A1 - Xiang, Anny H A1 - Choi, Hyeok Sun A1 - Cade, Brian E A1 - Tan, Jingyi A1 - Broadaway, K Alaine A1 - Williamson, Alice A1 - Kamali, Zoha A1 - Cui, Jinrui A1 - Thangam, Manonanthini A1 - Adair, Linda S A1 - Adeyemo, Adebowale A1 - Aguilar-Salinas, Carlos A A1 - Ahluwalia, Tarunveer S A1 - Anand, Sonia S A1 - Bertoni, Alain A1 - Bork-Jensen, Jette A1 - Brandslund, Ivan A1 - Buchanan, Thomas A A1 - Burant, Charles F A1 - Butterworth, Adam S A1 - Canouil, Mickaël A1 - Chan, Juliana C N A1 - Chang, Li-Ching A1 - Chee, Miao-Li A1 - Chen, Ji A1 - Chen, Shyh-Huei A1 - Chen, Yuan-Tsong A1 - Chen, Zhengming A1 - Chuang, Lee-Ming A1 - Cushman, Mary A1 - Danesh, John A1 - Das, Swapan K A1 - de Silva, H Janaka A1 - Dedoussis, George A1 - Dimitrov, Latchezar A1 - Doumatey, Ayo P A1 - Du, Shufa A1 - Duan, Qing A1 - Eckardt, Kai-Uwe A1 - Emery, Leslie S A1 - Evans, Daniel S A1 - Evans, Michele K A1 - Fischer, Krista A1 - Floyd, James S A1 - Ford, Ian A1 - Franco, Oscar H A1 - Frayling, Timothy M A1 - Freedman, Barry I A1 - Genter, Pauline A1 - Gerstein, Hertzel C A1 - Giedraitis, Vilmantas A1 - González-Villalpando, Clicerio A1 - Gonzalez-Villalpando, Maria Elena A1 - Gordon-Larsen, Penny A1 - Gross, Myron A1 - Guare, Lindsay A A1 - Hackinger, Sophie A1 - Hakaste, Liisa A1 - Han, Sohee A1 - Hattersley, Andrew T A1 - Herder, Christian A1 - Horikoshi, Momoko A1 - Howard, Annie-Green A1 - Hsueh, Willa A1 - Huang, Mengna A1 - Huang, Wei A1 - Hung, Yi-Jen A1 - Hwang, Mi Yeong A1 - Hwu, Chii-Min A1 - Ichihara, Sahoko A1 - Ikram, Mohammad Arfan A1 - Ingelsson, Martin A1 - Islam, Md Tariqul A1 - Isono, Masato A1 - Jang, Hye-Mi A1 - Jasmine, Farzana A1 - Jiang, Guozhi A1 - Jonas, Jost B A1 - Jørgensen, Torben A1 - Kamanu, Frederick K A1 - Kandeel, Fouad R A1 - Kasturiratne, Anuradhani A1 - Katsuya, Tomohiro A1 - Kaur, Varinderpal A1 - Kawaguchi, Takahisa A1 - Keaton, Jacob M A1 - Kho, Abel N A1 - Khor, Chiea-Chuen A1 - Kibriya, Muhammad G A1 - Kim, Duk-Hwan A1 - Kronenberg, Florian A1 - Kuusisto, Johanna A1 - Läll, Kristi A1 - Lange, Leslie A A1 - Lee, Kyung Min A1 - Lee, Myung-Shik A1 - Lee, Nanette R A1 - Leong, Aaron A1 - Li, Liming A1 - Li, Yun A1 - Li-Gao, Ruifang A1 - Ligthart, Symen A1 - Lindgren, Cecilia M A1 - Linneberg, Allan A1 - Liu, Ching-Ti A1 - Liu, Jianjun A1 - Locke, Adam E A1 - Louie, Tin A1 - Luan, Jian'an A1 - Luk, Andrea O A1 - Luo, Xi A1 - Lv, Jun A1 - Lynch, Julie A A1 - Lyssenko, Valeriya A1 - Maeda, Shiro A1 - Mamakou, Vasiliki A1 - Mansuri, Sohail Rafik A1 - Matsuda, Koichi A1 - Meitinger, Thomas A1 - Melander, Olle A1 - Metspalu, Andres A1 - Mo, Huan A1 - Morris, Andrew D A1 - Moura, Filipe A A1 - Nadler, Jerry L A1 - Nalls, Michael A A1 - Nayak, Uma A1 - Ntalla, Ioanna A1 - Okada, Yukinori A1 - Orozco, Lorena A1 - Patel, Sanjay R A1 - Patil, Snehal A1 - Pei, Pei A1 - Pereira, Mark A A1 - Peters, Annette A1 - Pirie, Fraser J A1 - Polikowsky, Hannah G A1 - Porneala, Bianca A1 - Prasad, Gauri A1 - Rasmussen-Torvik, Laura J A1 - Reiner, Alexander P A1 - Roden, Michael A1 - Rohde, Rebecca A1 - Roll, Katheryn A1 - Sabanayagam, Charumathi A1 - Sandow, Kevin A1 - Sankareswaran, Alagu A1 - Sattar, Naveed A1 - Schönherr, Sebastian A1 - Shahriar, Mohammad A1 - Shen, Botong A1 - Shi, Jinxiu A1 - Shin, Dong Mun A1 - Shojima, Nobuhiro A1 - Smith, Jennifer A A1 - So, Wing Yee A1 - Stančáková, Alena A1 - Steinthorsdottir, Valgerdur A1 - Stilp, Adrienne M A1 - Strauch, Konstantin A1 - Taylor, Kent D A1 - Thorand, Barbara A1 - Thorsteinsdottir, Unnur A1 - Tomlinson, Brian A1 - Tran, Tam C A1 - Tsai, Fuu-Jen A1 - Tuomilehto, Jaakko A1 - Tusié-Luna, Teresa A1 - Udler, Miriam S A1 - Valladares-Salgado, Adan A1 - van Dam, Rob M A1 - van Klinken, Jan B A1 - Varma, Rohit A1 - Wacher-Rodarte, Niels A1 - Wheeler, Eleanor A1 - Wickremasinghe, Ananda R A1 - van Dijk, Ko Willems A1 - Witte, Daniel R A1 - Yajnik, Chittaranjan S A1 - Yamamoto, Ken A1 - Yamamoto, Kenichi A1 - Yoon, Kyungheon A1 - Yu, Canqing A1 - Yuan, Jian-Min A1 - Yusuf, Salim A1 - Zawistowski, Matthew A1 - Zhang, Liang A1 - Zheng, Wei A1 - Raffel, Leslie J A1 - Igase, Michiya A1 - Ipp, Eli A1 - Redline, Susan A1 - Cho, Yoon Shin A1 - Lind, Lars A1 - Province, Michael A A1 - Fornage, Myriam A1 - Hanis, Craig L A1 - Ingelsson, Erik A1 - Zonderman, Alan B A1 - Psaty, Bruce M A1 - Wang, Ya-Xing A1 - Rotimi, Charles N A1 - Becker, Diane M A1 - Matsuda, Fumihiko A1 - Liu, Yongmei A1 - Yokota, Mitsuhiro A1 - Kardia, Sharon L R A1 - Peyser, Patricia A A1 - Pankow, James S A1 - Engert, James C A1 - Bonnefond, Amélie A1 - Froguel, Philippe A1 - Wilson, James G A1 - Sheu, Wayne H H A1 - Wu, Jer-Yuarn A1 - Hayes, M Geoffrey A1 - Ma, Ronald C W A1 - Wong, Tien-Yin A1 - Mook-Kanamori, Dennis O A1 - Tuomi, Tiinamaija A1 - Chandak, Giriraj R A1 - Collins, Francis S A1 - Bharadwaj, Dwaipayan A1 - Paré, Guillaume A1 - Sale, Michèle M A1 - Ahsan, Habibul A1 - Motala, Ayesha A A1 - Shu, Xiao-Ou A1 - Park, Kyong-Soo A1 - Jukema, J Wouter A1 - Cruz, Miguel A1 - Chen, Yii-Der Ida A1 - Rich, Stephen S A1 - McKean-Cowdin, Roberta A1 - Grallert, Harald A1 - Cheng, Ching-Yu A1 - Ghanbari, Mohsen A1 - Tai, E-Shyong A1 - Dupuis, Josée A1 - Kato, Norihiro A1 - Laakso, Markku A1 - Köttgen, Anna A1 - Koh, Woon-Puay A1 - Bowden, Donald W A1 - Palmer, Colin N A A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Liu, Simin A1 - North, Kari E A1 - Saleheen, Danish A1 - Hansen, Torben A1 - Pedersen, Oluf A1 - Wareham, Nicholas J A1 - Lee, Juyoung A1 - Kim, Bong-Jo A1 - Millwood, Iona Y A1 - Walters, Robin G A1 - Stefansson, Kari A1 - Ahlqvist, Emma A1 - Goodarzi, Mark O A1 - Mohlke, Karen L A1 - Langenberg, Claudia A1 - Haiman, Christopher A A1 - Loos, Ruth J F A1 - Florez, Jose C A1 - Rader, Daniel J A1 - Ritchie, Marylyn D A1 - Zöllner, Sebastian A1 - Mägi, Reedik A1 - Marston, Nicholas A A1 - Ruff, Christian T A1 - van Heel, David A A1 - Finer, Sarah A1 - Denny, Joshua C A1 - Yamauchi, Toshimasa A1 - Kadowaki, Takashi A1 - Chambers, John C A1 - Ng, Maggie C Y A1 - Sim, Xueling A1 - Below, Jennifer E A1 - Tsao, Philip S A1 - Chang, Kyong-Mi A1 - McCarthy, Mark I A1 - Meigs, James B A1 - Mahajan, Anubha A1 - Spracklen, Cassandra N A1 - Mercader, Josep M A1 - Boehnke, Michael A1 - Rotter, Jerome I A1 - Vujkovic, Marijana A1 - Voight, Benjamin F A1 - Morris, Andrew P A1 - Zeggini, Eleftheria AB -

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes and molecular mechanisms that are often specific to cell type. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

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