@article {6689, title = {Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease.}, journal = {Circ Cardiovasc Genet}, volume = {8}, year = {2015}, month = {2015 Apr}, pages = {351-5}, abstract = {

BACKGROUND: Histidine is a semiessential amino acid with antioxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels, and incident coronary heart disease (CHD) in a population-based sample.

METHODS AND RESULTS: By conducting whole exome sequencing on 1152 African Americans in the Atherosclerosis Risk in Communities (ARIC) study and focusing on loss-of-function (LoF) variants, we identified 3 novel rare LoF variants in HAL, a gene that encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (β=0.26; P=1.2{\texttimes}10(-13)). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1\%; P=1.2{\texttimes}10(-4)). In addition, high blood histidine levels were associated with reduced risk of developing incident CHD with an average of 21.5 years of follow-up among African Americans (hazard ratio=0.18; P=1.9{\texttimes}10(-4)). This finding was validated in an independent sample of European Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in HAL were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium.

CONCLUSIONS: Three LoF mutations in HAL were associated with increased histidine levels, which in turn were shown to be inversely related to the risk of CHD among both African Americans and European Americans. Future investigations on the association between HAL gene variation and CHD are warranted.

}, keywords = {Adult, African Americans, Alleles, Coronary Disease, European Continental Ancestry Group, Female, Histidine, Histidine Ammonia-Lyase, Humans, Male, Mutation}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.114.000697}, author = {Yu, Bing and Li, Alexander H and Muzny, Donna and Veeraraghavan, Narayanan and de Vries, Paul S and Bis, Joshua C and Musani, Solomon K and Alexander, Danny and Morrison, Alanna C and Franco, Oscar H and Uitterlinden, Andre and Hofman, Albert and Dehghan, Abbas and Wilson, James G and Psaty, Bruce M and Gibbs, Richard and Wei, Peng and Boerwinkle, Eric} } @article {6788, title = {Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF.}, journal = {Blood}, volume = {126}, year = {2015}, month = {2015 Sep 10}, pages = {e19-29}, abstract = {

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] >=0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.

}, keywords = {Cohort Studies, Factor VII, Factor VIII, Fibrinogen, Gene Frequency, Genetic Association Studies, Genetic Variation, Humans, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Potassium Channels, von Willebrand Factor}, issn = {1528-0020}, doi = {10.1182/blood-2015-02-624551}, author = {Huffman, Jennifer E and de Vries, Paul S and Morrison, Alanna C and Sabater-Lleal, Maria and Kacprowski, Tim and Auer, Paul L and Brody, Jennifer A and Chasman, Daniel I and Chen, Ming-Huei and Guo, Xiuqing and Lin, Li-An and Marioni, Riccardo E and M{\"u}ller-Nurasyid, Martina and Yanek, Lisa R and Pankratz, Nathan and Grove, Megan L and de Maat, Moniek P M and Cushman, Mary and Wiggins, Kerri L and Qi, Lihong and Sennblad, Bengt and Harris, Sarah E and Polasek, Ozren and Riess, Helene and Rivadeneira, Fernando and Rose, Lynda M and Goel, Anuj and Taylor, Kent D and Teumer, Alexander and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and Yao, Jie and Tang, Weihong and Levy, Daniel and Waldenberger, Melanie and Becker, Diane M and Folsom, Aaron R and Giulianini, Franco and Greinacher, Andreas and Hofman, Albert and Huang, Chiang-Ching and Kooperberg, Charles and Silveira, Angela and Starr, John M and Strauch, Konstantin and Strawbridge, Rona J and Wright, Alan F and McKnight, Barbara and Franco, Oscar H and Zakai, Neil and Mathias, Rasika A and Psaty, Bruce M and Ridker, Paul M and Tofler, Geoffrey H and V{\"o}lker, Uwe and Watkins, Hugh and Fornage, Myriam and Hamsten, Anders and Deary, Ian J and Boerwinkle, Eric and Koenig, Wolfgang and Rotter, Jerome I and Hayward, Caroline and Dehghan, Abbas and Reiner, Alex P and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L} } @article {6936, title = {A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.}, journal = {Hum Mol Genet}, volume = {25}, year = {2016}, month = {2016 Jan 15}, pages = {358-70}, abstract = {

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including \~{}120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3\% of the variance in plasma fibrinogen concentration.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddv454}, author = {de Vries, Paul S and Chasman, Daniel I and Sabater-Lleal, Maria and Chen, Ming-Huei and Huffman, Jennifer E and Steri, Maristella and Tang, Weihong and Teumer, Alexander and Marioni, Riccardo E and Grossmann, Vera and Hottenga, Jouke J and Trompet, Stella and M{\"u}ller-Nurasyid, Martina and Zhao, Jing Hua and Brody, Jennifer A and Kleber, Marcus E and Guo, Xiuqing and Wang, Jie Jin and Auer, Paul L and Attia, John R and Yanek, Lisa R and Ahluwalia, Tarunveer S and Lahti, Jari and Venturini, Cristina and Tanaka, Toshiko and Bielak, Lawrence F and Joshi, Peter K and Rocanin-Arjo, Ares and Kolcic, Ivana and Navarro, Pau and Rose, Lynda M and Oldmeadow, Christopher and Riess, Helene and Mazur, Johanna and Basu, Saonli and Goel, Anuj and Yang, Qiong and Ghanbari, Mohsen and Willemsen, Gonneke and Rumley, Ann and Fiorillo, Edoardo and de Craen, Anton J M and Grotevendt, Anne and Scott, Robert and Taylor, Kent D and Delgado, Graciela E and Yao, Jie and Kifley, Annette and Kooperberg, Charles and Qayyum, Rehan and Lopez, Lorna M and Berentzen, Tina L and R{\"a}ikk{\"o}nen, Katri and Mangino, Massimo and Bandinelli, Stefania and Peyser, Patricia A and Wild, Sarah and Tr{\'e}gou{\"e}t, David-Alexandre and Wright, Alan F and Marten, Jonathan and Zemunik, Tatijana and Morrison, Alanna C and Sennblad, Bengt and Tofler, Geoffrey and de Maat, Moniek P M and de Geus, Eco J C and Lowe, Gordon D and Zoledziewska, Magdalena and Sattar, Naveed and Binder, Harald and V{\"o}lker, Uwe and Waldenberger, Melanie and Khaw, Kay-Tee and McKnight, Barbara and Huang, Jie and Jenny, Nancy S and Holliday, Elizabeth G and Qi, Lihong and Mcevoy, Mark G and Becker, Diane M and Starr, John M and Sarin, Antti-Pekka and Hysi, Pirro G and Hernandez, Dena G and Jhun, Min A and Campbell, Harry and Hamsten, Anders and Rivadeneira, Fernando and McArdle, Wendy L and Slagboom, P Eline and Zeller, Tanja and Koenig, Wolfgang and Psaty, Bruce M and Haritunians, Talin and Liu, Jingmin and Palotie, Aarno and Uitterlinden, Andr{\'e} G and Stott, David J and Hofman, Albert and Franco, Oscar H and Polasek, Ozren and Rudan, Igor and Morange, Pierre-Emmanuel and Wilson, James F and Kardia, Sharon L R and Ferrucci, Luigi and Spector, Tim D and Eriksson, Johan G and Hansen, Torben and Deary, Ian J and Becker, Lewis C and Scott, Rodney J and Mitchell, Paul and M{\"a}rz, Winfried and Wareham, Nick J and Peters, Annette and Greinacher, Andreas and Wild, Philipp S and Jukema, J Wouter and Boomsma, Dorret I and Hayward, Caroline and Cucca, Francesco and Tracy, Russell and Watkins, Hugh and Reiner, Alex P and Folsom, Aaron R and Ridker, Paul M and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Strachan, David P and Dehghan, Abbas} } @article {7343, title = {Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study.}, journal = {PLoS One}, volume = {12}, year = {2017}, month = {2017}, pages = {e0167742}, abstract = {

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals. We identified six additional signals using 1000G imputation, while 29 loci were associated using both HapMap and 1000G imputation. One locus identified using HapMap imputation was not significant using 1000G imputation. The genome-wide significance threshold of 5{\texttimes}10-8 is based on the number of independent statistical tests using HapMap imputation, and 1000G imputation may lead to further independent tests that should be corrected for. When using a stricter Bonferroni correction for the 1000G GWA study (P-value < 2.5{\texttimes}10-8), the number of loci significant only using HapMap imputation increased to 4 while the number of loci significant only using 1000G decreased to 5. In conclusion, 1000G imputation enabled the identification of 20\% more loci than HapMap imputation, although the advantage of 1000G imputation became less clear when a stricter Bonferroni correction was used. More generally, our results provide insights that are applicable to the implementation of other dense reference panels that are under development.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0167742}, author = {de Vries, Paul S and Sabater-Lleal, Maria and Chasman, Daniel I and Trompet, Stella and Ahluwalia, Tarunveer S and Teumer, Alexander and Kleber, Marcus E and Chen, Ming-Huei and Wang, Jie Jin and Attia, John R and Marioni, Riccardo E and Steri, Maristella and Weng, Lu-Chen and Pool, Rene and Grossmann, Vera and Brody, Jennifer A and Venturini, Cristina and Tanaka, Toshiko and Rose, Lynda M and Oldmeadow, Christopher and Mazur, Johanna and Basu, Saonli and Fr{\r a}nberg, Mattias and Yang, Qiong and Ligthart, Symen and Hottenga, Jouke J and Rumley, Ann and Mulas, Antonella and de Craen, Anton J M and Grotevendt, Anne and Taylor, Kent D and Delgado, Graciela E and Kifley, Annette and Lopez, Lorna M and Berentzen, Tina L and Mangino, Massimo and Bandinelli, Stefania and Morrison, Alanna C and Hamsten, Anders and Tofler, Geoffrey and de Maat, Moniek P M and Draisma, Harmen H M and Lowe, Gordon D and Zoledziewska, Magdalena and Sattar, Naveed and Lackner, Karl J and V{\"o}lker, Uwe and McKnight, Barbara and Huang, Jie and Holliday, Elizabeth G and McEvoy, Mark A and Starr, John M and Hysi, Pirro G and Hernandez, Dena G and Guan, Weihua and Rivadeneira, Fernando and McArdle, Wendy L and Slagboom, P Eline and Zeller, Tanja and Psaty, Bruce M and Uitterlinden, Andr{\'e} G and de Geus, Eco J C and Stott, David J and Binder, Harald and Hofman, Albert and Franco, Oscar H and Rotter, Jerome I and Ferrucci, Luigi and Spector, Tim D and Deary, Ian J and M{\"a}rz, Winfried and Greinacher, Andreas and Wild, Philipp S and Cucca, Francesco and Boomsma, Dorret I and Watkins, Hugh and Tang, Weihong and Ridker, Paul M and Jukema, Jan W and Scott, Rodney J and Mitchell, Paul and Hansen, Torben and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Strachan, David P and Dehghan, Abbas} } @article {7588, title = {Genome-Wide Interactions with Dairy Intake for Body Mass Index in Adults of European Descent.}, journal = {Mol Nutr Food Res}, year = {2017}, month = {2017 Sep 21}, abstract = {

SCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption.

METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3{\textquoteright} of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 {\texttimes} 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure.

CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.

}, issn = {1613-4133}, doi = {10.1002/mnfr.201700347}, author = {Smith, Caren E and Follis, Jack L and Dashti, Hassan S and Tanaka, Toshiko and Graff, Mariaelisa and Fretts, Amanda M and Kilpel{\"a}inen, Tuomas O and Wojczynski, Mary K and Richardson, Kris and Nalls, Mike A and Schulz, Christina-Alexandra and Liu, Yongmei and Frazier-Wood, Alexis C and van Eekelen, Esther and Wang, Carol and de Vries, Paul S and Mikkil{\"a}, Vera and Rohde, Rebecca and Psaty, Bruce M and Hansen, Torben and Feitosa, Mary F and Lai, Chao-Qiang and Houston, Denise K and Ferruci, Luigi and Ericson, Ulrika and Wang, Zhe and de Mutsert, Ren{\'e}e and Oddy, Wendy H and de Jonge, Ester A L and Sepp{\"a}l{\"a}, Ilkka and Justice, Anne E and Lemaitre, Rozenn N and S{\o}rensen, Thorkild I A and Province, Michael A and Parnell, Laurence D and Garcia, Melissa E and Bandinelli, Stefania and Orho-Melander, Marju and Rich, Stephen S and Rosendaal, Frits R and Pennell, Craig E and Kiefte-de Jong, Jessica C and K{\"a}h{\"o}nen, Mika and Young, Kristin L and Pedersen, Oluf and Aslibekyan, Stella and Rotter, Jerome I and Mook-Kanamori, Dennis O and Zillikens, M Carola and Raitakari, Olli T and North, Kari E and Overvad, Kim and Arnett, Donna K and Hofman, Albert and Lehtim{\"a}ki, Terho and Tj{\o}nneland, Anne and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Franco, Oscar H and German, J Bruce and Siscovick, David S and Cupples, L Adrienne and Ordovas, Jose M} } @article {7816, title = {DNA methylation age is associated with an altered hemostatic profile in a multi-ethnic meta-analysis.}, journal = {Blood}, year = {2018}, month = {2018 Jul 24}, abstract = {

Many hemostatic factors are associated with age and age-related diseases, however much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we used European and African-ancestry participants who were meta-analyzed separately and combined via a random effects meta-analysis. All other measures only included participants of European-ancestry. We found that 1-year higher extrinsic epigenetic age as compared to chronological age was associated with higher fibrinogen (0.004 g/L per year; 95\% CI: 0.001, 0.007; P = 0.01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL per year; 95\% CI: 0.07, 0.20; P = 6.6x10-5) concentrations as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the three fibrinogen subunit-encoding genes (FGA, FGG, and FGB), in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a pro-coagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

}, issn = {1528-0020}, doi = {10.1182/blood-2018-02-831347}, author = {Ward-Caviness, Cavin K and Huffman, Jennifer E and Evertt, Karl and Germain, Marine and van Dongen, Jenny and Hill, W David and Jhun, Min A and Brody, Jennifer A and Ghanbari, Mohsen and Du, Lei and Roetker, Nicholas S and de Vries, Paul S and Waldenberger, Melanie and Gieger, Christian and Wolf, Petra and Prokisch, Holger and Koenig, Wolfgang and O{\textquoteright}Donnell, Christopher J and Levy, Daniel and Liu, Chunyu and Truong, Vinh and Wells, Philip S and Tr{\'e}gou{\"e}t, David-Alexandre and Tang, Weihong and Morrison, Alanna C and Boerwinkle, Eric and Wiggins, Kerri L and McKnight, Barbara and Guo, Xiuqing and Psaty, Bruce M and Sotoodenia, Nona and Boomsa, Dorret I and Willemsen, Gonneke and Ligthart, Lannie and Deary, Ian J and Zhao, Wei and Ware, Erin B and Kardia, Sharon L R and van Meurs, Joyce B J and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Eriksson, Per and Franco-Cereceda, Anders and Pankow, James S and Johnson, Andrew D and Gagnon, France and Morange, Pierre-Emmanuel and de Geus, Eco J C and Starr, John M and Smith, Jennifer A and Dehghan, Abbas and Bj{\"o}rck, Hanna M and Smith, Nicholas L and Peters, Annette} } @article {7920, title = {Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 Nov 01}, pages = {691-706}, abstract = {

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5~{\texttimes} 10). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0\% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.09.009}, author = {Ligthart, Symen and Vaez, Ahmad and V{\~o}sa, Urmo and Stathopoulou, Maria G and de Vries, Paul S and Prins, Bram P and van der Most, Peter J and Tanaka, Toshiko and Naderi, Elnaz and Rose, Lynda M and Wu, Ying and Karlsson, Robert and Barbalic, Maja and Lin, Honghuang and Pool, Rene and Zhu, Gu and Mace, Aurelien and Sidore, Carlo and Trompet, Stella and Mangino, Massimo and Sabater-Lleal, Maria and Kemp, John P and Abbasi, Ali and Kacprowski, Tim and Verweij, Niek and Smith, Albert V and Huang, Tao and Marzi, Carola and Feitosa, Mary F and Lohman, Kurt K and Kleber, Marcus E and Milaneschi, Yuri and Mueller, Christian and Huq, Mahmudul and Vlachopoulou, Efthymia and Lyytik{\"a}inen, Leo-Pekka and Oldmeadow, Christopher and Deelen, Joris and Perola, Markus and Zhao, Jing Hua and Feenstra, Bjarke and Amini, Marzyeh and Lahti, Jari and Schraut, Katharina E and Fornage, Myriam and Suktitipat, Bhoom and Chen, Wei-Min and Li, Xiaohui and Nutile, Teresa and Malerba, Giovanni and Luan, Jian{\textquoteright}an and Bak, Tom and Schork, Nicholas and del Greco M, Fabiola and Thiering, Elisabeth and Mahajan, Anubha and Marioni, Riccardo E and Mihailov, Evelin and Eriksson, Joel and Ozel, Ayse Bilge and Zhang, Weihua and Nethander, Maria and Cheng, Yu-Ching and Aslibekyan, Stella and Ang, Wei and Gandin, Ilaria and Yengo, Loic and Portas, Laura and Kooperberg, Charles and Hofer, Edith and Rajan, Kumar B and Schurmann, Claudia and den Hollander, Wouter and Ahluwalia, Tarunveer S and Zhao, Jing and Draisma, Harmen H M and Ford, Ian and Timpson, Nicholas and Teumer, Alexander and Huang, Hongyan and Wahl, Simone and Liu, Yongmei and Huang, Jie and Uh, Hae-Won and Geller, Frank and Joshi, Peter K and Yanek, Lisa R and Trabetti, Elisabetta and Lehne, Benjamin and Vozzi, Diego and Verbanck, Marie and Biino, Ginevra and Saba, Yasaman and Meulenbelt, Ingrid and O{\textquoteright}Connell, Jeff R and Laakso, Markku and Giulianini, Franco and Magnusson, Patrik K E and Ballantyne, Christie M and Hottenga, Jouke Jan and Montgomery, Grant W and Rivadineira, Fernando and Rueedi, Rico and Steri, Maristella and Herzig, Karl-Heinz and Stott, David J and Menni, Cristina and Fr{\r a}nberg, Mattias and St Pourcain, Beate and Felix, Stephan B and Pers, Tune H and Bakker, Stephan J L and Kraft, Peter and Peters, Annette and Vaidya, Dhananjay and Delgado, Graciela and Smit, Johannes H and Gro{\ss}mann, Vera and Sinisalo, Juha and Sepp{\"a}l{\"a}, Ilkka and Williams, Stephen R and Holliday, Elizabeth G and Moed, Matthijs and Langenberg, Claudia and R{\"a}ikk{\"o}nen, Katri and Ding, Jingzhong and Campbell, Harry and Sale, Mich{\`e}le M and Chen, Yii-der I and James, Alan L and Ruggiero, Daniela and Soranzo, Nicole and Hartman, Catharina A and Smith, Erin N and Berenson, Gerald S and Fuchsberger, Christian and Hernandez, Dena and Tiesler, Carla M T and Giedraitis, Vilmantas and Liewald, David and Fischer, Krista and Mellstr{\"o}m, Dan and Larsson, Anders and Wang, Yunmei and Scott, William R and Lorentzon, Matthias and Beilby, John and Ryan, Kathleen A and Pennell, Craig E and Vuckovic, Dragana and Balkau, Beverly and Concas, Maria Pina and Schmidt, Reinhold and Mendes de Leon, Carlos F and Bottinger, Erwin P and Kloppenburg, Margreet and Paternoster, Lavinia and Boehnke, Michael and Musk, A W and Willemsen, Gonneke and Evans, David M and Madden, Pamela A F and K{\"a}h{\"o}nen, Mika and Kutalik, Zolt{\'a}n and Zoledziewska, Magdalena and Karhunen, Ville and Kritchevsky, Stephen B and Sattar, Naveed and Lachance, Genevieve and Clarke, Robert and Harris, Tamara B and Raitakari, Olli T and Attia, John R and van Heemst, Diana and Kajantie, Eero and Sorice, Rossella and Gambaro, Giovanni and Scott, Robert A and Hicks, Andrew A and Ferrucci, Luigi and Standl, Marie and Lindgren, Cecilia M and Starr, John M and Karlsson, Magnus and Lind, Lars and Li, Jun Z and Chambers, John C and Mori, Trevor A and de Geus, Eco J C N and Heath, Andrew C and Martin, Nicholas G and Auvinen, Juha and Buckley, Brendan M and de Craen, Anton J M and Waldenberger, Melanie and Strauch, Konstantin and Meitinger, Thomas and Scott, Rodney J and McEvoy, Mark and Beekman, Marian and Bombieri, Cristina and Ridker, Paul M and Mohlke, Karen L and Pedersen, Nancy L and Morrison, Alanna C and Boomsma, Dorret I and Whitfield, John B and Strachan, David P and Hofman, Albert and Vollenweider, Peter and Cucca, Francesco and Jarvelin, Marjo-Riitta and Jukema, J Wouter and Spector, Tim D and Hamsten, Anders and Zeller, Tanja and Uitterlinden, Andr{\'e} G and Nauck, Matthias and Gudnason, Vilmundur and Qi, Lu and Grallert, Harald and Borecki, Ingrid B and Rotter, Jerome I and M{\"a}rz, Winfried and Wild, Philipp S and Lokki, Marja-Liisa and Boyle, Michael and Salomaa, Veikko and Melbye, Mads and Eriksson, Johan G and Wilson, James F and Penninx, Brenda W J H and Becker, Diane M and Worrall, Bradford B and Gibson, Greg and Krauss, Ronald M and Ciullo, Marina and Zaza, Gianluigi and Wareham, Nicholas J and Oldehinkel, Albertine J and Palmer, Lyle J and Murray, Sarah S and Pramstaller, Peter P and Bandinelli, Stefania and Heinrich, Joachim and Ingelsson, Erik and Deary, Ian J and M{\"a}gi, Reedik and Vandenput, Liesbeth and van der Harst, Pim and Desch, Karl C and Kooner, Jaspal S and Ohlsson, Claes and Hayward, Caroline and Lehtim{\"a}ki, Terho and Shuldiner, Alan R and Arnett, Donna K and Beilin, Lawrence J and Robino, Antonietta and Froguel, Philippe and Pirastu, Mario and Jess, Tine and Koenig, Wolfgang and Loos, Ruth J F and Evans, Denis A and Schmidt, Helena and Smith, George Davey and Slagboom, P Eline and Eiriksdottir, Gudny and Morris, Andrew P and Psaty, Bruce M and Tracy, Russell P and Nolte, Ilja M and Boerwinkle, Eric and Visvikis-Siest, Sophie and Reiner, Alex P and Gross, Myron and Bis, Joshua C and Franke, Lude and Franco, Oscar H and Benjamin, Emelia J and Chasman, Daniel I and Dupuis, Jos{\'e}e and Snieder, Harold and Dehghan, Abbas and Alizadeh, Behrooz Z} } @article {7924, title = {Genome-Wide Association Trans-Ethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.}, journal = {Circulation}, year = {2018}, month = {2018 Nov 20}, abstract = {

BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

METHODS: We meta-analyzed genome-wide association results from 46,354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated approximately 35 million imputed variants with natural-log transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization (MR) analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

RESULTS: We identified 13 novel genome-wide significant (p<=2.5x10) associations; 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. MR suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.034532}, author = {Sabater-Lleal, Maria and Huffman, Jennifer E and de Vries, Paul S and Marten, Jonathan and Mastrangelo, Michael A and Song, Ci and Pankratz, Nathan and Ward-Caviness, Cavin K and Yanek, Lisa R and Trompet, Stella and Delgado, Graciela E and Guo, Xiuqing and Bartz, Traci M and Martinez-Perez, Angel and Germain, Marine and de Haan, Hugoline G and Ozel, Ayse B and Polasek, Ozren and Smith, Albert V and Eicher, John D and Reiner, Alex P and Tang, Weihong and Davies, Neil M and Stott, David J and Rotter, Jerome I and Tofler, Geoffrey H and Boerwinkle, Eric and de Maat, Moniek P M and Kleber, Marcus E and Welsh, Paul and Brody, Jennifer A and Chen, Ming-Huei and Vaidya, Dhananjay and Soria, Jos{\'e} Manuel and Suchon, Pierre and van Hylckama Vlieg, Astrid and Desch, Karl C and Kolcic, Ivana and Joshi, Peter K and Launer, Lenore J and Harris, Tamara B and Campbell, Harry and Rudan, Igor and Becker, Diane M and Li, Jun Z and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Hofman, Albert and Franco, Oscar H and Cushman, Mary and Psaty, Bruce M and Morange, Pierre-Emmanuel and McKnight, Barbara and Chong, Michael R and Fernandez-Cadenas, Israel and Rosand, Jonathan and Lindgren, Arne and Gudnason, Vilmundur and Wilson, James F and Hayward, Caroline and Ginsburg, David and Fornage, Myriam and Rosendaal, Frits R and Souto, Juan Carlos and Becker, Lewis C and Jenny, Nancy S and M{\"a}rz, Winfried and Jukema, J Wouter and Dehghan, Abbas and Tr{\'e}gou{\"e}t, David-Alexandre and Morrison, Alanna C and Johnson, Andrew D and O{\textquoteright}Donnell, Christopher J and Strachan, David P and Lowenstein, Charles J and Smith, Nicholas L} } @article {7913, title = {GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 12 03}, pages = {5141}, abstract = {

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans.

}, keywords = {ADAMTS9 Protein, Amino Acid Oxidoreductases, Carotid Intima-Media Thickness, Coronary Disease, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Lod Score, Plaque, Atherosclerotic, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-018-07340-5}, author = {Franceschini, Nora and Giambartolomei, Claudia and de Vries, Paul S and Finan, Chris and Bis, Joshua C and Huntley, Rachael P and Lovering, Ruth C and Tajuddin, Salman M and Winkler, Thomas W and Graff, Misa and Kavousi, Maryam and Dale, Caroline and Smith, Albert V and Hofer, Edith and van Leeuwen, Elisabeth M and Nolte, Ilja M and Lu, Lingyi and Scholz, Markus and Sargurupremraj, Muralidharan and Pitk{\"a}nen, Niina and Franz{\'e}n, Oscar and Joshi, Peter K and Noordam, Raymond and Marioni, Riccardo E and Hwang, Shih-Jen and Musani, Solomon K and Schminke, Ulf and Palmas, Walter and Isaacs, Aaron and Correa, Adolfo and Zonderman, Alan B and Hofman, Albert and Teumer, Alexander and Cox, Amanda J and Uitterlinden, Andr{\'e} G and Wong, Andrew and Smit, Andries J and Newman, Anne B and Britton, Annie and Ruusalepp, Arno and Sennblad, Bengt and Hedblad, Bo and Pasaniuc, Bogdan and Penninx, Brenda W and Langefeld, Carl D and Wassel, Christina L and Tzourio, Christophe and Fava, Cristiano and Baldassarre, Damiano and O{\textquoteright}Leary, Daniel H and Teupser, Daniel and Kuh, Diana and Tremoli, Elena and Mannarino, Elmo and Grossi, Enzo and Boerwinkle, Eric and Schadt, Eric E and Ingelsson, Erik and Veglia, Fabrizio and Rivadeneira, Fernando and Beutner, Frank and Chauhan, Ganesh and Heiss, Gerardo and Snieder, Harold and Campbell, Harry and V{\"o}lzke, Henry and Markus, Hugh S and Deary, Ian J and Jukema, J Wouter and de Graaf, Jacqueline and Price, Jacqueline and Pott, Janne and Hopewell, Jemma C and Liang, Jingjing and Thiery, Joachim and Engmann, Jorgen and Gertow, Karl and Rice, Kenneth and Taylor, Kent D and Dhana, Klodian and Kiemeney, Lambertus A L M and Lind, Lars and Raffield, Laura M and Launer, Lenore J and Holdt, Lesca M and D{\"o}rr, Marcus and Dichgans, Martin and Traylor, Matthew and Sitzer, Matthias and Kumari, Meena and Kivimaki, Mika and Nalls, Mike A and Melander, Olle and Raitakari, Olli and Franco, Oscar H and Rueda-Ochoa, Oscar L and Roussos, Panos and Whincup, Peter H and Amouyel, Philippe and Giral, Philippe and Anugu, Pramod and Wong, Quenna and Malik, Rainer and Rauramaa, Rainer and Burkhardt, Ralph and Hardy, Rebecca and Schmidt, Reinhold and de Mutsert, Ren{\'e}e and Morris, Richard W and Strawbridge, Rona J and Wannamethee, S Goya and H{\"a}gg, Sara and Shah, Sonia and McLachlan, Stela and Trompet, Stella and Seshadri, Sudha and Kurl, Sudhir and Heckbert, Susan R and Ring, Susan and Harris, Tamara B and Lehtim{\"a}ki, Terho and Galesloot, Tessel E and Shah, Tina and de Faire, Ulf and Plagnol, Vincent and Rosamond, Wayne D and Post, Wendy and Zhu, Xiaofeng and Zhang, Xiaoling and Guo, Xiuqing and Saba, Yasaman and Dehghan, Abbas and Seldenrijk, Adrie and Morrison, Alanna C and Hamsten, Anders and Psaty, Bruce M and van Duijn, Cornelia M and Lawlor, Deborah A and Mook-Kanamori, Dennis O and Bowden, Donald W and Schmidt, Helena and Wilson, James F and Wilson, James G and Rotter, Jerome I and Wardlaw, Joanna M and Deanfield, John and Halcox, Julian and Lyytik{\"a}inen, Leo-Pekka and Loeffler, Markus and Evans, Michele K and Debette, Stephanie and Humphries, Steve E and V{\"o}lker, Uwe and Gudnason, Vilmundur and Hingorani, Aroon D and Bj{\"o}rkegren, Johan L M and Casas, Juan P and O{\textquoteright}Donnell, Christopher J} } @article {7988, title = {A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.}, journal = {Blood}, volume = {133}, year = {2019}, month = {2019 Feb 28}, pages = {967-977}, abstract = {

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a -ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel ( and ) and 6 known loci associated with FVII activity, explaining 19.0\% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing in HuH7 cells upregulated FVII, whereas silencing downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at and contribute to FVII activity by regulating expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

}, issn = {1528-0020}, doi = {10.1182/blood-2018-05-849240}, author = {de Vries, Paul S and Sabater-Lleal, Maria and Huffman, Jennifer E and Marten, Jonathan and Song, Ci and Pankratz, Nathan and Bartz, Traci M and de Haan, Hugoline G and Delgado, Graciela E and Eicher, John D and Martinez-Perez, Angel and Ward-Caviness, Cavin K and Brody, Jennifer A and Chen, Ming-Huei and de Maat, Moniek P M and Fr{\r a}nberg, Mattias and Gill, Dipender and Kleber, Marcus E and Rivadeneira, Fernando and Soria, Jos{\'e} Manuel and Tang, Weihong and Tofler, Geoffrey H and Uitterlinden, Andr{\'e} G and van Hylckama Vlieg, Astrid and Seshadri, Sudha and Boerwinkle, Eric and Davies, Neil M and Giese, Anne-Katrin and Ikram, M Kamran and Kittner, Steven J and McKnight, Barbara and Psaty, Bruce M and Reiner, Alex P and Sargurupremraj, Muralidharan and Taylor, Kent D and Fornage, Myriam and Hamsten, Anders and M{\"a}rz, Winfried and Rosendaal, Frits R and Souto, Juan Carlos and Dehghan, Abbas and Johnson, Andrew D and Morrison, Alanna C and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L} } @article {8200, title = {Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.}, journal = {Blood}, volume = {134}, year = {2019}, month = {2019 Nov 07}, pages = {1645-1657}, abstract = {

Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.

}, issn = {1528-0020}, doi = {10.1182/blood.2019000435}, author = {Lindstr{\"o}m, Sara and Wang, Lu and Smith, Erin N and Gordon, William and van Hylckama Vlieg, Astrid and de Andrade, Mariza and Brody, Jennifer A and Pattee, Jack W and Haessler, Jeffrey and Brumpton, Ben M and Chasman, Daniel I and Suchon, Pierre and Chen, Ming-Huei and Turman, Constance and Germain, Marine and Wiggins, Kerri L and MacDonald, James and Braekkan, Sigrid K and Armasu, Sebastian M and Pankratz, Nathan and Jackson, Rebecca D and Nielsen, Jonas B and Giulianini, Franco and Puurunen, Marja K and Ibrahim, Manal and Heckbert, Susan R and Damrauer, Scott M and Natarajan, Pradeep and Klarin, Derek and de Vries, Paul S and Sabater-Lleal, Maria and Huffman, Jennifer E and Bammler, Theo K and Frazer, Kelly A and McCauley, Bryan M and Taylor, Kent and Pankow, James S and Reiner, Alexander P and Gabrielsen, Maiken E and Deleuze, Jean-Francois and O{\textquoteright}Donnell, Chris J and Kim, Jihye and McKnight, Barbara and Kraft, Peter and Hansen, John-Bjarne and Rosendaal, Frits R and Heit, John A and Psaty, Bruce M and Tang, Weihong and Kooperberg, Charles and Hveem, Kristian and Ridker, Paul M and Morange, Pierre-Emmanuel and Johnson, Andrew D and Kabrhel, Christopher and Tr{\'e}gou{\"e}t, David-Alexandre and Smith, Nicholas L} } @article {8205, title = {Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Oct 03}, pages = {706-718}, abstract = {

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12\% in African-Americans, MAF = 2\% in Hispanics) lowered HbA1c (-0.88\% in hemizygous males, -0.34\% in heterozygous females) and explained 23\% of HbA1c variance in African-Americans and 4\% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5\%; -0.98\% in hemizygous males, -0.46\% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.08.010}, author = {Sarnowski, Chloe and Leong, Aaron and Raffield, Laura M and Wu, Peitao and de Vries, Paul S and DiCorpo, Daniel and Guo, Xiuqing and Xu, Huichun and Liu, Yongmei and Zheng, Xiuwen and Hu, Yao and Brody, Jennifer A and Goodarzi, Mark O and Hidalgo, Bertha A and Highland, Heather M and Jain, Deepti and Liu, Ching-Ti and Naik, Rakhi P and O{\textquoteright}Connell, Jeffrey R and Perry, James A and Porneala, Bianca C and Selvin, Elizabeth and Wessel, Jennifer and Psaty, Bruce M and Curran, Joanne E and Peralta, Juan M and Blangero, John and Kooperberg, Charles and Mathias, Rasika and Johnson, Andrew D and Reiner, Alexander P and Mitchell, Braxton D and Cupples, L Adrienne and Vasan, Ramachandran S and Correa, Adolfo and Morrison, Alanna C and Boerwinkle, Eric and Rotter, Jerome I and Rich, Stephen S and Manning, Alisa K and Dupuis, Jos{\'e}e and Meigs, James B} } @article {8050, title = {Mendelian randomization evaluation of causal effects of fibrinogen on incident coronary heart disease.}, journal = {PLoS One}, volume = {14}, year = {2019}, month = {2019}, pages = {e0216222}, abstract = {

BACKGROUND: Fibrinogen is an essential hemostatic factor and cardiovascular disease risk factor. Early attempts at evaluating the causal effect of fibrinogen on coronary heart disease (CHD) and myocardial infraction (MI) using Mendelian randomization (MR) used single variant approaches, and did not take advantage of recent genome-wide association studies (GWAS) or multi-variant, pleiotropy robust MR methodologies.

METHODS AND FINDINGS: We evaluated evidence for a causal effect of fibrinogen on both CHD and MI using MR. We used both an allele score approach and pleiotropy robust MR models. The allele score was composed of 38 fibrinogen-associated variants from recent GWAS. Initial analyses using the allele score used a meta-analysis of 11 European-ancestry prospective cohorts, free of CHD and MI at baseline, to examine incidence CHD and MI. We also applied 2 sample MR methods with data from a prevalent CHD and MI GWAS. Results are given in terms of the hazard ratio (HR) or odds ratio (OR), depending on the study design, and associated 95\% confidence interval (CI). In single variant analyses no causal effect of fibrinogen on CHD or MI was observed. In multi-variant analyses using incidence CHD cases and the allele score approach, the estimated causal effect (HR) of a 1 g/L higher fibrinogen concentration was 1.62 (CI = 1.12, 2.36) when using incident cases and the allele score approach. In 2 sample MR analyses that accounted for pleiotropy, the causal estimate (OR) was reduced to 1.18 (CI = 0.98, 1.42) and 1.09 (CI = 0.89, 1.33) in the 2 most precise (smallest CI) models, out of 4 models evaluated. In the 2 sample MR analyses for MI, there was only very weak evidence of a causal effect in only 1 out of 4 models.

CONCLUSIONS: A small causal effect of fibrinogen on CHD is observed using multi-variant MR approaches which account for pleiotropy, but not single variant MR approaches. Taken together, results indicate that even with large sample sizes and multi-variant approaches MR analyses still cannot exclude the null when estimating the causal effect of fibrinogen on CHD, but that any potential causal effect is likely to be much smaller than observed in epidemiological studies.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0216222}, author = {Ward-Caviness, Cavin K and de Vries, Paul S and Wiggins, Kerri L and Huffman, Jennifer E and Yanek, Lisa R and Bielak, Lawrence F and Giulianini, Franco and Guo, Xiuqing and Kleber, Marcus E and Kacprowski, Tim and Gro{\ss}, Stefan and Petersman, Astrid and Davey Smith, George and Hartwig, Fernando P and Bowden, Jack and Hemani, Gibran and M{\"u}ller-Nuraysid, Martina and Strauch, Konstantin and Koenig, Wolfgang and Waldenberger, Melanie and Meitinger, Thomas and Pankratz, Nathan and Boerwinkle, Eric and Tang, Weihong and Fu, Yi-Ping and Johnson, Andrew D and Song, Ci and de Maat, Moniek P M and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Brody, Jennifer A and McKnight, Barbara and Chen, Yii-Der Ida and Psaty, Bruce M and Mathias, Rasika A and Becker, Diane M and Peyser, Patricia A and Smith, Jennifer A and Bielinski, Suzette J and Ridker, Paul M and Taylor, Kent D and Yao, Jie and Tracy, Russell and Delgado, Graciela and Trompet, Stella and Sattar, Naveed and Jukema, J Wouter and Becker, Lewis C and Kardia, Sharon L R and Rotter, Jerome I and M{\"a}rz, Winfried and D{\"o}rr, Marcus and Chasman, Daniel I and Dehghan, Abbas and O{\textquoteright}Donnell, Christopher J and Smith, Nicholas L and Peters, Annette and Morrison, Alanna C} } @article {7970, title = {Multi-Ancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.}, journal = {Am J Epidemiol}, year = {2019}, month = {2019 Jan 29}, abstract = {

An individual{\textquoteright}s lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P~<~1~{\texttimes}~10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P~<~5~{\texttimes}~10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

}, issn = {1476-6256}, doi = {10.1093/aje/kwz005}, author = {de Vries, Paul S and Brown, Michael R and Bentley, Amy R and Sung, Yun J and Winkler, Thomas W and Ntalla, Ioanna and Schwander, Karen and Kraja, Aldi T and Guo, Xiuqing and Franceschini, Nora and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Huffman, Jennifer E and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Richard, Melissa A and Noordam, Raymond and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Deng, Xuan and Dorajoo, Rajkumar and Lohman, Kurt K and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Evangelou, Evangelos and Graff, Mariaelisa and Alver, Maris and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Gandin, Ilaria and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and Hartwig, Fernando P and He, Meian and Horimoto, Andrea R V R and Hsu, Fang-Chi and Jackson, Anne U and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Laguzzi, Federica and Lee, Joseph H and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Matoba, Nana and Nolte, Ilja M and Pietzner, Maik and Riaz, Muhammad and Said, M Abdullah and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Wang, Yajuan and Ware, Erin B and Wen, Wanqing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Aung, Tin and Ballantyne, Christie and Boerwinkle, Eric and Broeckel, Ulrich and Campbell, Archie and Canouil, Micka{\"e}l and Charumathi, Sabanayagam and Chen, Yii-Der Ida and Connell, John M and de Faire, Ulf and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Silva, H Janaka and Ding, Jingzhong and Dominiczak, Anna F and Duan, Qing and Eaton, Charles B and Eppinga, Ruben N and Faul, Jessica D and Fisher, Virginia and Forrester, Terrence and Franco, Oscar H and Friedlander, Yechiel and Ghanbari, Mohsen and Giulianini, Franco and Grabe, Hans J and Grove, Megan L and Gu, C Charles and Harris, Tamara B and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hixson, James E and Howard, Barbara V and Ikram, M Arfan and Jacobs, David R and Johnson, Craig and Jonas, Jost Bruno and Kammerer, Candace M and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Koistinen, Heikki A and Kolcic, Ivana and Kooperberg, Charles and Krieger, Jose E and Kritchevsky, Steve B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lemaitre, Rozenn N and Li, Yize and Liang, Jingjing and Liu, Jianjun and Liu, Kiang and Loh, Marie and Louie, Tin and M{\"a}gi, Reedik and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Mosley, Thomas H and Mukamal, Kenneth J and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and Sotoodehnia, Nona and O{\textquoteright}Connell, Jeff R and Palmer, Nicholette D and Pazoki, Raha and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Poulter, Neil and Raffel, Leslie J and Raitakari, Olli T and Reiner, Alex P and Rice, Treva K and Rich, Stephen S and Robino, Antonietta and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Sever, Peter and Shi, Yuan and Sidney, Stephen and Sims, Mario and Smith, Blair H and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Tan, Nicholas and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Vuckovic, Dragana and Waldenberger, Melanie and Wang, Lihua and Wang, Yujie and Wang, Zhe and Wei, Wen Bin and Williams, Christine and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Yu, Bing and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Deary, Ian J and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo L and Kamatani, Yoichiro and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Penninx, Brenda and Pereira, Alexandre C and Rauramaa, Rainer and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wang, Ya Xing and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Zheng, Wei and Elliott, Paul and North, Kari E and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Liu, Ching-Ti and Liu, Yongmei and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Kardia, Sharon L R and Zhu, Xiaofeng and Rotimi, Charles N and Mook-Kanamori, Dennis O and Fornage, Myriam and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Liu, Jingmin and Rotter, Jerome I and Gauderman, W James and Province, Michael A and Munroe, Patricia B and Rice, Kenneth and Chasman, Daniel I and Cupples, L Adrienne and Rao, Dabeeru C and Morrison, Alanna C} } @article {8005, title = {Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Apr}, pages = {636-648}, abstract = {

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.

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0378-y}, author = {Bentley, Amy R and Sung, Yun J and Brown, Michael R and Winkler, Thomas W and Kraja, Aldi T and Ntalla, Ioanna and Schwander, Karen and Chasman, Daniel I and Lim, Elise and Deng, Xuan and Guo, Xiuqing and Liu, Jingmin and Lu, Yingchang and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Huffman, Jennifer E and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Richard, Melissa A and Noordam, Raymond and Baker, Jenna and Chen, Guanjie and Aschard, Hugues and Bartz, Traci M and Ding, Jingzhong and Dorajoo, Rajkumar and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Zhao, Wei and Graff, Mariaelisa and Alver, Maris and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and Hartwig, Fernando P and He, Meian and Horimoto, Andrea R V R and Hsu, Fang-Chi and Hung, Yi-Jen and Jackson, Anne U and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Leander, Karin and Lin, Keng-Hung and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Matoba, Nana and Nolte, Ilja M and Pietzner, Maik and Prins, Bram and Riaz, Muhammad and Robino, Antonietta and Said, M Abdullah and Schupf, Nicole and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Wang, Tzung-Dau and Wang, Yajuan and Ware, Erin B and Wen, Wanqing and Xiang, Yong-Bing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Adeyemo, Adebowale and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Arzumanyan, Zorayr and Aung, Tin and Ballantyne, Christie and Barr, R Graham and Bielak, Lawrence F and Boerwinkle, Eric and Bottinger, Erwin P and Broeckel, Ulrich and Brown, Morris and Cade, Brian E and Campbell, Archie and Canouil, Micka{\"e}l and Charumathi, Sabanayagam and Chen, Yii-Der Ida and Christensen, Kaare and Concas, Maria Pina and Connell, John M and de Las Fuentes, Lisa and de Silva, H Janaka and de Vries, Paul S and Doumatey, Ayo and Duan, Qing and Eaton, Charles B and Eppinga, Ruben N and Faul, Jessica D and Floyd, James S and Forouhi, Nita G and Forrester, Terrence and Friedlander, Yechiel and Gandin, Ilaria and Gao, He and Ghanbari, Mohsen and Gharib, Sina A and Gigante, Bruna and Giulianini, Franco and Grabe, Hans J and Gu, C Charles and Harris, Tamara B and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hixson, James E and Ikram, M Arfan and Jia, Yucheng and Joehanes, Roby and Johnson, Craig and Jonas, Jost Bruno and Justice, Anne E and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Kolcic, Ivana and Kooperberg, Charles and Krieger, Jose E and Kritchevsky, Stephen B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Liang, Jingjing and Lin, Shiow and Liu, Ching-Ti and Liu, Jianjun and Liu, Kiang and Loh, Marie and Lohman, Kurt K and Louie, Tin and Luzzi, Anna and M{\"a}gi, Reedik and Mahajan, Anubha and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Momozawa, Yukihide and Morris, Andrew P and Murray, Alison D and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Papanicolau, George J and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Poulter, Neil and Raitakari, Olli T and Reiner, Alex P and Renstrom, Frida and Rice, Treva K and Rich, Stephen S and Robinson, Jennifer G and Rose, Lynda M and Rosendaal, Frits R and Rudan, Igor and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Sever, Peter and Shi, Yuan and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Stringham, Heather M and Tan, Nicholas Y Q and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Tiemeier, Henning and Turner, Stephen T and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Waldenberger, Melanie and Wang, Heming and Wang, Lan and Wang, Lihua and Wei, Wen Bin and Williams, Christine A and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Young, Kristin and Yu, Caizheng and Yuan, Jian-Min and Zhou, Jie and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Cooper, Richard S and de Faire, Ulf and Deary, Ian J and Elliott, Paul and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo L and Juang, Jyh-Ming Jimmy and Kamatani, Yoichiro and Kammerer, Candace M and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Laurie, Cathy C and Lee, I-Te and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Pereira, Alexandre C and Rauramaa, Rainer and Redline, Susan and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wang, Jun-Sing and Wang, Ya Xing and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zeggini, Eleftheria and Zheng, Wei and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon L R and Liu, Yongmei and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Mook-Kanamori, Dennis O and Fornage, Myriam and Province, Michael A and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Loos, Ruth J F and Franceschini, Nora and Rotter, Jerome I and Zhu, Xiaofeng and Bierut, Laura J and Gauderman, W James and Rice, Kenneth and Munroe, Patricia B and Morrison, Alanna C and Rao, Dabeeru C and Rotimi, Charles N and Cupples, L Adrienne} } @article {8202, title = {Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Nov 12}, pages = {5121}, abstract = {

Both short and long sleep are associated with an adverse lipid profile, likely through different biological pathways. To elucidate the biology of sleep-associated adverse lipid profile, we conduct multi-ancestry genome-wide sleep-SNP interaction analyses on three lipid traits (HDL-c, LDL-c and triglycerides). In the total study sample (discovery + replication) of 126,926 individuals from 5 different ancestry groups, when considering either long or short total sleep time interactions in joint analyses, we identify 49 previously unreported lipid loci, and 10 additional previously unreported lipid loci in a restricted sample of European-ancestry cohorts. In addition, we identify new gene-sleep interactions for known lipid loci such as LPL and PCSK9. The previously unreported lipid loci have a modest explained variance in lipid levels: most notable, gene-short-sleep interactions explain 4.25\% of the variance in triglyceride level. Collectively, these findings contribute to our understanding of the biological mechanisms involved in sleep-associated adverse lipid profiles.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-12958-0}, author = {Noordam, Raymond and Bos, Maxime M and Wang, Heming and Winkler, Thomas W and Bentley, Amy R and Kilpel{\"a}inen, Tuomas O and de Vries, Paul S and Sung, Yun Ju and Schwander, Karen and Cade, Brian E and Manning, Alisa and Aschard, Hugues and Brown, Michael R and Chen, Han and Franceschini, Nora and Musani, Solomon K and Richard, Melissa and Vojinovic, Dina and Aslibekyan, Stella and Bartz, Traci M and de Las Fuentes, Lisa and Feitosa, Mary and Horimoto, Andrea R and Ilkov, Marjan and Kho, Minjung and Kraja, Aldi and Li, Changwei and Lim, Elise and Liu, Yongmei and Mook-Kanamori, Dennis O and Rankinen, Tuomo and Tajuddin, Salman M and van der Spek, Ashley and Wang, Zhe and Marten, Jonathan and Laville, Vincent and Alver, Maris and Evangelou, Evangelos and Graff, Maria E and He, Meian and Kuhnel, Brigitte and Lyytik{\"a}inen, Leo-Pekka and Marques-Vidal, Pedro and Nolte, Ilja M and Palmer, Nicholette D and Rauramaa, Rainer and Shu, Xiao-Ou and Snieder, Harold and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Adolfo, Correa and Ballantyne, Christie and Bielak, Larry and Biermasz, Nienke R and Boerwinkle, Eric and Dimou, Niki and Eiriksdottir, Gudny and Gao, Chuan and Gharib, Sina A and Gottlieb, Daniel J and Haba-Rubio, Jos{\'e} and Harris, Tamara B and Heikkinen, Sami and Heinzer, Raphael and Hixson, James E and Homuth, Georg and Ikram, M Arfan and Komulainen, Pirjo and Krieger, Jose E and Lee, Jiwon and Liu, Jingmin and Lohman, Kurt K and Luik, Annemarie I and M{\"a}gi, Reedik and Martin, Lisa W and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Nalls, Mike A and O{\textquoteright}Connell, Jeff and Peters, Annette and Peyser, Patricia and Raitakari, Olli T and Reiner, Alex P and Rensen, Patrick C N and Rice, Treva K and Rich, Stephen S and Roenneberg, Till and Rotter, Jerome I and Schreiner, Pamela J and Shikany, James and Sidney, Stephen S and Sims, Mario and Sitlani, Colleen M and Sofer, Tamar and Strauch, Konstantin and Swertz, Morris A and Taylor, Kent D and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and V{\"o}lzke, Henry and Waldenberger, Melanie and Wallance, Robert B and van Dijk, Ko Willems and Yu, Caizheng and Zonderman, Alan B and Becker, Diane M and Elliott, Paul and Esko, T{\~o}nu and Gieger, Christian and Grabe, Hans J and Lakka, Timo A and Lehtim{\"a}ki, Terho and North, Kari E and Penninx, Brenda W J H and Vollenweider, Peter and Wagenknecht, Lynne E and Wu, Tangchun and Xiang, Yong-Bing and Zheng, Wei and Arnett, Donna K and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon and Kelly, Tanika N and Kritchevsky, Stephen B and Loos, Ruth J F and Pereira, Alexandre C and Province, Mike and Psaty, Bruce M and Rotimi, Charles and Zhu, Xiaofeng and Amin, Najaf and Cupples, L Adrienne and Fornage, Myriam and Fox, Ervin F and Guo, Xiuqing and Gauderman, W James and Rice, Kenneth and Kooperberg, Charles and Munroe, Patricia B and Liu, Ching-Ti and Morrison, Alanna C and Rao, Dabeeru C and van Heemst, Diana and Redline, Susan} } @article {7976, title = {Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 01 22}, pages = {376}, abstract = {

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Brazil, Calcium-Binding Proteins, Cholesterol, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Exercise, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Hispanic Americans, Humans, LIM-Homeodomain Proteins, Lipid Metabolism, Lipids, Male, Membrane Proteins, Microtubule-Associated Proteins, Middle Aged, Muscle Proteins, Nerve Tissue Proteins, Transcription Factors, Triglycerides, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-018-08008-w}, author = {Kilpel{\"a}inen, Tuomas O and Bentley, Amy R and Noordam, Raymond and Sung, Yun Ju and Schwander, Karen and Winkler, Thomas W and Jakupovi{\'c}, Hermina and Chasman, Daniel I and Manning, Alisa and Ntalla, Ioanna and Aschard, Hugues and Brown, Michael R and de Las Fuentes, Lisa and Franceschini, Nora and Guo, Xiuqing and Vojinovic, Dina and Aslibekyan, Stella and Feitosa, Mary F and Kho, Minjung and Musani, Solomon K and Richard, Melissa and Wang, Heming and Wang, Zhe and Bartz, Traci M and Bielak, Lawrence F and Campbell, Archie and Dorajoo, Rajkumar and Fisher, Virginia and Hartwig, Fernando P and Horimoto, Andrea R V R and Li, Changwei and Lohman, Kurt K and Marten, Jonathan and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Alver, Maris and Amini, Marzyeh and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Graff, Mariaelisa and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Jackson, Anne U and Zhao, Jing Hua and Kraja, Aldi T and Kuhnel, Brigitte and Laguzzi, Federica and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Rauramaa, Rainer and Riaz, Muhammad and Robino, Antonietta and Rueedi, Rico and Stringham, Heather M and Takeuchi, Fumihiko and van der Most, Peter J and Varga, Tibor V and Verweij, Niek and Ware, Erin B and Wen, Wanqing and Li, Xiaoyin and Yanek, Lisa R and Amin, Najaf and Arnett, Donna K and Boerwinkle, Eric and Brumat, Marco and Cade, Brian and Canouil, Micka{\"e}l and Chen, Yii-Der Ida and Concas, Maria Pina and Connell, John and de Mutsert, Ren{\'e}e and de Silva, H Janaka and de Vries, Paul S and Demirkan, Ayse and Ding, Jingzhong and Eaton, Charles B and Faul, Jessica D and Friedlander, Yechiel and Gabriel, Kelley P and Ghanbari, Mohsen and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven C and Ikram, M Arfan and Jonas, Jost B and Koh, Woon-Puay and Komulainen, Pirjo and Krieger, Jose E and Kritchevsky, Stephen B and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Leander, Karin and Lemaitre, Rozenn N and Lewis, Cora E and Liang, Jingjing and Liu, Jianjun and M{\"a}gi, Reedik and Manichaikul, Ani and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Mohlke, Karen L and Mosley, Thomas H and Murray, Alison D and Nalls, Mike A and Nang, Ei-Ei Khaing and Nelson, Christopher P and Nona, Sotoodehnia and Norris, Jill M and Nwuba, Chiamaka Vivian and O{\textquoteright}Connell, Jeff and Palmer, Nicholette D and Papanicolau, George J and Pazoki, Raha and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Porteous, David J and Poveda, Alaitz and Raitakari, Olli T and Rich, Stephen S and Risch, Neil and Robinson, Jennifer G and Rose, Lynda M and Rudan, Igor and Schreiner, Pamela J and Scott, Robert A and Sidney, Stephen S and Sims, Mario and Smith, Jennifer A and Snieder, Harold and Sofer, Tamar and Starr, John M and Sternfeld, Barbara and Strauch, Konstantin and Tang, Hua and Taylor, Kent D and Tsai, Michael Y and Tuomilehto, Jaakko and Uitterlinden, Andr{\'e} G and van der Ende, M Yldau and van Heemst, Diana and Voortman, Trudy and Waldenberger, Melanie and Wennberg, Patrik and Wilson, Gregory and Xiang, Yong-Bing and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and de Faire, Ulf and Deary, Ian J and Elliott, Paul and Esko, T{\~o}nu and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Kato, Norihiro and Laakso, Markku and Lakka, Timo A and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Samani, Nilesh J and Shu, Xiao-Ou and van der Harst, Pim and van Vliet-Ostaptchouk, Jana V and Vollenweider, Peter and Wagenknecht, Lynne E and Wang, Ya X and Wareham, Nicholas J and Weir, David R and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Evans, Michele K and Franks, Paul W and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kelly, Tanika N and Liu, Yongmei and North, Kari E and Pereira, Alexandre C and Ridker, Paul M and Tai, E Shyong and van Dam, Rob M and Fox, Ervin R and Kardia, Sharon L R and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Province, Michael A and Redline, Susan and van Duijn, Cornelia M and Rotter, Jerome I and Kooperberg, Charles B and Gauderman, W James and Psaty, Bruce M and Rice, Kenneth and Munroe, Patricia B and Fornage, Myriam and Cupples, L Adrienne and Rotimi, Charles N and Morrison, Alanna C and Rao, Dabeeru C and Loos, Ruth J F} } @article {8381, title = {Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.}, journal = {Mol Psychiatry}, year = {2020}, month = {2020 May 05}, abstract = {

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 {\texttimes} 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

}, issn = {1476-5578}, doi = {10.1038/s41380-020-0719-3}, author = {de Las Fuentes, Lisa and Sung, Yun Ju and Noordam, Raymond and Winkler, Thomas and Feitosa, Mary F and Schwander, Karen and Bentley, Amy R and Brown, Michael R and Guo, Xiuqing and Manning, Alisa and Chasman, Daniel I and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Campbell, Archie and Cheng, Ching-Yu and Dorajoo, Rajkumar and Hartwig, Fernando P and Horimoto, A R V R and Li, Changwei and Li-Gao, Ruifang and Liu, Yongmei and Marten, Jonathan and Musani, Solomon K and Ntalla, Ioanna and Rankinen, Tuomo and Richard, Melissa and Sim, Xueling and Smith, Albert V and Tajuddin, Salman M and Tayo, Bamidele O and Vojinovic, Dina and Warren, Helen R and Xuan, Deng and Alver, Maris and Boissel, Mathilde and Chai, Jin-Fang and Chen, Xu and Christensen, Kaare and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Girotto, Giorgia and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Kuhnel, Brigitte and Laguzzi, Federica and Li, Xiaoyin and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Poveda, Alaitz and Rauramaa, Rainer and Riaz, Muhammad and Rueedi, Rico and Shu, Xiao-Ou and Snieder, Harold and Sofer, Tamar and Takeuchi, Fumihiko and Verweij, Niek and Ware, Erin B and Weiss, Stefan and Yanek, Lisa R and Amin, Najaf and Arking, Dan E and Arnett, Donna K and Bergmann, Sven and Boerwinkle, Eric and Brody, Jennifer A and Broeckel, Ulrich and Brumat, Marco and Burke, Gregory and Cabrera, Claudia P and Canouil, Micka{\"e}l and Chee, Miao Li and Chen, Yii-Der Ida and Cocca, Massimiliano and Connell, John and de Silva, H Janaka and de Vries, Paul S and Eiriksdottir, Gudny and Faul, Jessica D and Fisher, Virginia and Forrester, Terrence and Fox, Ervin F and Friedlander, Yechiel and Gao, He and Gigante, Bruna and Giulianini, Franco and Gu, Chi Charles and Gu, Dongfeng and Harris, Tamara B and He, Jiang and Heikkinen, Sami and Heng, Chew-Kiat and Hunt, Steven and Ikram, M Arfan and Irvin, Marguerite R and K{\"a}h{\"o}nen, Mika and Kavousi, Maryam and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Komulainen, Pirjo and Kraja, Aldi T and Krieger, J E and Langefeld, Carl D and Li, Yize and Liang, Jingjing and Liewald, David C M and Liu, Ching-Ti and Liu, Jianjun and Lohman, Kurt K and M{\"a}gi, Reedik and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mook-Kanamori, Dennis O and Nalls, Mike A and Nelson, Christopher P and Norris, Jill M and O{\textquoteright}Connell, Jeff and Ogunniyi, Adesola and Padmanabhan, Sandosh and Palmer, Nicholette D and Pedersen, Nancy L and Perls, Thomas and Peters, Annette and Petersmann, Astrid and Peyser, Patricia A and Polasek, Ozren and Porteous, David J and Raffel, Leslie J and Rice, Treva K and Rotter, Jerome I and Rudan, Igor and Rueda-Ochoa, Oscar-Leonel and Sabanayagam, Charumathi and Salako, Babatunde L and Schreiner, Pamela J and Shikany, James M and Sidney, Stephen S and Sims, Mario and Sitlani, Colleen M and Smith, Jennifer A and Starr, John M and Strauch, Konstantin and Swertz, Morris A and Teumer, Alexander and Tham, Yih Chung and Uitterlinden, Andr{\'e} G and Vaidya, Dhananjay and van der Ende, M Yldau and Waldenberger, Melanie and Wang, Lihua and Wang, Ya-Xing and Wei, Wen-Bin and Weir, David R and Wen, Wanqing and Yao, Jie and Yu, Bing and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Zonderman, Alan B and Becker, Diane M and Bowden, Donald W and Deary, Ian J and D{\"o}rr, Marcus and Esko, T{\~o}nu and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Jonas, Jost Bruno and Kammerer, Candace M and Kato, Norihiro and Lakka, Timo A and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Marques-Vidal, Pedro and Penninx, Brenda W J H and Samani, Nilesh J and van der Harst, Pim and Wagenknecht, Lynne E and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Bouchard, Claude and Cooper, Richard S and Correa, Adolfo and Evans, Michele K and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kelly, Tanika N and Kritchevsky, Stephen B and Levy, Daniel and Palmas, Walter R and Pereira, A C and Province, Michael M and Psaty, Bruce M and Ridker, Paul M and Rotimi, Charles N and Tai, E Shyong and van Dam, Rob M and van Duijn, Cornelia M and Wong, Tien Yin and Rice, Kenneth and Gauderman, W James and Morrison, Alanna C and North, Kari E and Kardia, Sharon L R and Caulfield, Mark J and Elliott, Paul and Munroe, Patricia B and Franks, Paul W and Rao, Dabeeru C and Fornage, Myriam} } @article {8625, title = {Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.}, journal = {PLoS One}, volume = {15}, year = {2020}, month = {2020}, pages = {e0230035}, abstract = {

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome.

METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95\% confidence interval: 1.43, 2.27; P = 7.12 {\texttimes} 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) >= 5 and variants with minor allele frequency (MAF) < 5\%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event.

CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

}, keywords = {Aging, Coronary Artery Disease, Cross-Sectional Studies, Europe, European Continental Ancestry Group, Genetic Loci, Genome-Wide Association Study, Humans, Myocardial Infarction, Polymorphism, Single Nucleotide, Prospective Studies}, issn = {1932-6203}, doi = {10.1371/journal.pone.0230035}, author = {Hahn, Julie and Fu, Yi-Ping and Brown, Michael R and Bis, Joshua C and de Vries, Paul S and Feitosa, Mary F and Yanek, Lisa R and Weiss, Stefan and Giulianini, Franco and Smith, Albert Vernon and Guo, Xiuqing and Bartz, Traci M and Becker, Diane M and Becker, Lewis C and Boerwinkle, Eric and Brody, Jennifer A and Chen, Yii-Der Ida and Franco, Oscar H and Grove, Megan and Harris, Tamara B and Hofman, Albert and Hwang, Shih-Jen and Kral, Brian G and Launer, Lenore J and Markus, Marcello R P and Rice, Kenneth M and Rich, Stephen S and Ridker, Paul M and Rivadeneira, Fernando and Rotter, Jerome I and Sotoodehnia, Nona and Taylor, Kent D and Uitterlinden, Andr{\'e} G and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Yao, Jie and Chasman, Daniel I and D{\"o}rr, Marcus and Gudnason, Vilmundur and Mathias, Rasika A and Post, Wendy and Psaty, Bruce M and Dehghan, Abbas and O{\textquoteright}Donnell, Christopher J and Morrison, Alanna C} } @article {8407, title = {Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 Aug}, pages = {e002772}, abstract = {

BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, <=5\%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65{\texttimes}10 for the interaction test) and replicated at nominal significance level (=0.013) in .

CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002772}, author = {Wang, Zhe and Chen, Han and Bartz, Traci M and Bielak, Lawrence F and Chasman, Daniel I and Feitosa, Mary F and Franceschini, Nora and Guo, Xiuqing and Lim, Elise and Noordam, Raymond and Richard, Melissa A and Wang, Heming and Cade, Brian and Cupples, L Adrienne and de Vries, Paul S and Giulanini, Franco and Lee, Jiwon and Lemaitre, Rozenn N and Martin, Lisa W and Reiner, Alex P and Rich, Stephen S and Schreiner, Pamela J and Sidney, Stephen and Sitlani, Colleen M and Smith, Jennifer A and Willems van Dijk, Ko and Yao, Jie and Zhao, Wei and Fornage, Myriam and Kardia, Sharon L R and Kooperberg, Charles and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Province, Michael A and Psaty, Bruce M and Redline, Susan and Ridker, Paul M and Rotter, Jerome I and Boerwinkle, Eric and Morrison, Alanna C} } @article {8711, title = {Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 04 12}, pages = {2182}, abstract = {

Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 {\texttimes} 10), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 {\texttimes} 10), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 {\texttimes} 10). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.

}, issn = {2041-1723}, doi = {10.1038/s41467-021-22339-1}, author = {Natarajan, Pradeep and Pampana, Akhil and Graham, Sarah E and Ruotsalainen, Sanni E and Perry, James A and de Vries, Paul S and Broome, Jai G and Pirruccello, James P and Honigberg, Michael C and Aragam, Krishna and Wolford, Brooke and Brody, Jennifer A and Antonacci-Fulton, Lucinda and Arden, Moscati and Aslibekyan, Stella and Assimes, Themistocles L and Ballantyne, Christie M and Bielak, Lawrence F and Bis, Joshua C and Cade, Brian E and Do, Ron and Doddapaneni, Harsha and Emery, Leslie S and Hung, Yi-Jen and Irvin, Marguerite R and Khan, Alyna T and Lange, Leslie and Lee, Jiwon and Lemaitre, Rozenn N and Martin, Lisa W and Metcalf, Ginger and Montasser, May E and Moon, Jee-Young and Muzny, Donna and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peralta, Juan M and Peyser, Patricia A and Stilp, Adrienne M and Tsai, Michael and Wang, Fei Fei and Weeks, Daniel E and Yanek, Lisa R and Wilson, James G and Abecasis, Goncalo and Arnett, Donna K and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Chang, Yi-Cheng and Chen, Yii-der I and Choi, Won Jung and Correa, Adolfo and Curran, Joanne E and Daly, Mark J and Dutcher, Susan K and Ellinor, Patrick T and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Germer, Soren and Gibbs, Richard A and He, Jiang and Hveem, Kristian and Jarvik, Gail P and Kaplan, Robert C and Kardia, Sharon L R and Kenny, Eimear and Kim, Ryan W and Kooperberg, Charles and Laurie, Cathy C and Lee, Seonwook and Lloyd-Jones, Don M and Loos, Ruth J F and Lubitz, Steven A and Mathias, Rasika A and Martinez, Karine A Viaud and McGarvey, Stephen T and Mitchell, Braxton D and Nickerson, Deborah A and North, Kari E and Palotie, Aarno and Park, Cheol Joo and Psaty, Bruce M and Rao, D C and Redline, Susan and Reiner, Alexander P and Seo, Daekwan and Seo, Jeong-Sun and Smith, Albert V and Tracy, Russell P and Vasan, Ramachandran S and Kathiresan, Sekar and Cupples, L Adrienne and Rotter, Jerome I and Morrison, Alanna C and Rich, Stephen S and Ripatti, Samuli and Willer, Cristen and Peloso, Gina M} } @article {8791, title = {FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.}, journal = {J Thromb Haemost}, year = {2021}, month = {2021 Apr 20}, abstract = {

BACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.

OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.

METHODS: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n~=~15~603), tPA (n~=~6876,) and D-dimer (n~=~19~306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.

RESULTS: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P~<~5~{\texttimes}~10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P~<~1~{\texttimes}~10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.

CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.

}, issn = {1538-7836}, doi = {10.1111/jth.15345}, author = {Thibord, Florian and Song, Ci and Pattee, Jack and Rodriguez, Benjamin A T and Chen, Ming-Huei and O{\textquoteright}Donnell, Christopher J and Kleber, Marcus E and Delgado, Graciela E and Guo, Xiuqing and Yao, Jie and Taylor, Kent D and Ozel, Ayse Bilge and Brody, Jennifer A and McKnight, Barbara and Gyorgy, Beata and Simonsick, Eleanor and Leonard, Hampton L and Carrasquilla, Germ{\'a}n D and Guindo-Martinez, Marta and Silveira, Angela and Temprano-Sagrera, Gerard and Yanek, Lisa R and Becker, Diane M and Mathias, Rasika A and Becker, Lewis C and Raffield, Laura M and Kilpel{\"a}inen, Tuomas O and Grarup, Niels and Pedersen, Oluf and Hansen, Torben and Linneberg, Allan and Hamsten, Anders and Watkins, Hugh and Sabater-Lleal, Maria and Nalls, Mike A and Tr{\'e}gou{\"e}t, David-Alexandre and Morange, Pierre-Emmanuel and Psaty, Bruce M and Tracy, Russel P and Smith, Nicholas L and Desch, Karl C and Cushman, Mary and Rotter, Jerome I and de Vries, Paul S and Pankratz, Nathan D and Folsom, Aaron R and Morrison, Alanna C and M{\"a}rz, Winfried and Tang, Weihong and Johnson, Andrew D} } @article {9005, title = {Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.}, journal = {HGG Adv}, volume = {2}, year = {2021}, month = {2021 Jan 14}, abstract = {

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (), synaptic function and neurotransmission (), as well as genes previously implicated in neuropsychiatric or stress-related disorders (). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

}, issn = {2666-2477}, doi = {10.1016/j.xhgg.2020.100013}, author = {Sun, Daokun and Richard, Melissa and Musani, Solomon K and Sung, Yun Ju and Winkler, Thomas W and Schwander, Karen and Chai, Jin Fang and Guo, Xiuqing and Kilpel{\"a}inen, Tuomas O and Vojinovic, Dina and Aschard, Hugues and Bartz, Traci M and Bielak, Lawrence F and Brown, Michael R and Chitrala, Kumaraswamy and Hartwig, Fernando P and Horimoto, Andrea R V R and Liu, Yongmei and Manning, Alisa K and Noordam, Raymond and Smith, Albert V and Harris, Sarah E and Kuhnel, Brigitte and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Rauramaa, Rainer and van der Most, Peter J and Wang, Rujia and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Arking, Dan E and Arnett, Donna K and Barac, Ana and Boerwinkle, Eric and Broeckel, Ulrich and Chakravarti, Aravinda and Chen, Yii-Der Ida and Cupples, L Adrienne and Davigulus, Martha L and de Las Fuentes, Lisa and de Mutsert, Ren{\'e}e and de Vries, Paul S and Delaney, Joseph A C and Roux, Ana V Diez and D{\"o}rr, Marcus and Faul, Jessica D and Fretts, Amanda M and Gallo, Linda C and Grabe, Hans J{\"o}rgen and Gu, C Charles and Harris, Tamara B and Hartman, Catharina C A and Heikkinen, Sami and Ikram, M Arfan and Isasi, Carmen and Johnson, W Craig and Jonas, Jost Bruno and Kaplan, Robert C and Komulainen, Pirjo and Krieger, Jose E and Levy, Daniel and Liu, Jianjun and Lohman, Kurt and Luik, Annemarie I and Martin, Lisa W and Meitinger, Thomas and Milaneschi, Yuri and O{\textquoteright}Connell, Jeff R and Palmas, Walter R and Peters, Annette and Peyser, Patricia A and Pulkki-R{\r a}back, Laura and Raffel, Leslie J and Reiner, Alex P and Rice, Kenneth and Robinson, Jennifer G and Rosendaal, Frits R and Schmidt, Carsten Oliver and Schreiner, Pamela J and Schwettmann, Lars and Shikany, James M and Shu, Xiao-Ou and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Sotoodehnia, Nona and Strauch, Konstantin and Tai, E Shyong and Taylor, Kent and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Waldenberger, Melanie and Wee, Hwee-Lin and Wei, Wen-Bin and Wilson, Gregory and Xuan, Deng and Yao, Jie and Zeng, Donglin and Zhao, Wei and Zhu, Xiaofeng and Zonderman, Alan B and Becker, Diane M and Deary, Ian J and Gieger, Christian and Lakka, Timo A and Lehtim{\"a}ki, Terho and North, Kari E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Snieder, Harold and Wang, Ya-Xing and Weir, David R and Zheng, Wei and Evans, Michele K and Gauderman, W James and Gudnason, Vilmundur and Horta, Bernardo L and Liu, Ching-Ti and Mook-Kanamori, Dennis O and Morrison, Alanna C and Pereira, Alexandre C and Psaty, Bruce M and Amin, Najaf and Fox, Ervin R and Kooperberg, Charles and Sim, Xueling and Bierut, Laura and Rotter, Jerome I and Kardia, Sharon L R and Franceschini, Nora and Rao, Dabeeru C and Fornage, Myriam} } @article {8714, title = {Multi-ancestry genome-wide gene-sleep interactions identify novel loci for blood pressure.}, journal = {Mol Psychiatry}, year = {2021}, month = {2021 Apr 15}, abstract = {

Long and short sleep duration are associated with elevated blood pressure (BP), possibly through effects on molecular pathways that influence neuroendocrine and vascular systems. To gain new insights into the genetic basis of sleep-related BP variation, we performed genome-wide gene by short or long sleep duration interaction analyses on four BP traits (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) across five ancestry groups in two stages using 2 degree of freedom (df) joint test followed by 1df test of interaction effects. Primary multi-ancestry analysis in 62,969 individuals in stage 1 identified three novel gene by sleep interactions that were replicated in an additional 59,296 individuals in stage 2 (stage 1 + 2 P < 5 {\texttimes} 10), including rs7955964 (FIGNL2/ANKRD33) that increases BP among long sleepers, and rs73493041 (SNORA26/C9orf170) and rs10406644 (KCTD15/LSM14A) that increase BP among short sleepers (P < 5 {\texttimes} 10). Secondary ancestry-specific analysis identified another novel gene by long sleep interaction at rs111887471 (TRPC3/KIAA1109) in individuals of African ancestry (P = 2 {\texttimes} 10). Combined stage 1 and 2 analyses additionally identified significant gene by long sleep interactions at 10 loci including MKLN1 and RGL3/ELAVL3 previously associated with BP, and significant gene by short sleep interactions at 10 loci including C2orf43 previously associated with BP (P < 10). 2df test also identified novel loci for BP after modeling sleep that has known functions in sleep-wake regulation, nervous and cardiometabolic systems. This study indicates that sleep and primary mechanisms regulating BP may interact to elevate BP level, suggesting novel insights into sleep-related BP regulation.

}, issn = {1476-5578}, doi = {10.1038/s41380-021-01087-0}, author = {Wang, Heming and Noordam, Raymond and Cade, Brian E and Schwander, Karen and Winkler, Thomas W and Lee, Jiwon and Sung, Yun Ju and Bentley, Amy R and Manning, Alisa K and Aschard, Hugues and Kilpel{\"a}inen, Tuomas O and Ilkov, Marjan and Brown, Michael R and Horimoto, Andrea R and Richard, Melissa and Bartz, Traci M and Vojinovic, Dina and Lim, Elise and Nierenberg, Jovia L and Liu, Yongmei and Chitrala, Kumaraswamynaidu and Rankinen, Tuomo and Musani, Solomon K and Franceschini, Nora and Rauramaa, Rainer and Alver, Maris and Zee, Phyllis C and Harris, Sarah E and van der Most, Peter J and Nolte, Ilja M and Munroe, Patricia B and Palmer, Nicholette D and Kuhnel, Brigitte and Weiss, Stefan and Wen, Wanqing and Hall, Kelly A and Lyytik{\"a}inen, Leo-Pekka and O{\textquoteright}Connell, Jeff and Eiriksdottir, Gudny and Launer, Lenore J and de Vries, Paul S and Arking, Dan E and Chen, Han and Boerwinkle, Eric and Krieger, Jose E and Schreiner, Pamela J and Sidney, Stephen and Shikany, James M and Rice, Kenneth and Chen, Yii-Der Ida and Gharib, Sina A and Bis, Joshua C and Luik, Annemarie I and Ikram, M Arfan and Uitterlinden, Andr{\'e} G and Amin, Najaf and Xu, Hanfei and Levy, Daniel and He, Jiang and Lohman, Kurt K and Zonderman, Alan B and Rice, Treva K and Sims, Mario and Wilson, Gregory and Sofer, Tamar and Rich, Stephen S and Palmas, Walter and Yao, Jie and Guo, Xiuqing and Rotter, Jerome I and Biermasz, Nienke R and Mook-Kanamori, Dennis O and Martin, Lisa W and Barac, Ana and Wallace, Robert B and Gottlieb, Daniel J and Komulainen, Pirjo and Heikkinen, Sami and M{\"a}gi, Reedik and Milani, Lili and Metspalu, Andres and Starr, John M and Milaneschi, Yuri and Waken, R J and Gao, Chuan and Waldenberger, Melanie and Peters, Annette and Strauch, Konstantin and Meitinger, Thomas and Roenneberg, Till and V{\"o}lker, Uwe and D{\"o}rr, Marcus and Shu, Xiao-Ou and Mukherjee, Sutapa and Hillman, David R and K{\"a}h{\"o}nen, Mika and Wagenknecht, Lynne E and Gieger, Christian and Grabe, Hans J and Zheng, Wei and Palmer, Lyle J and Lehtim{\"a}ki, Terho and Gudnason, Vilmundur and Morrison, Alanna C and Pereira, Alexandre C and Fornage, Myriam and Psaty, Bruce M and van Duijn, Cornelia M and Liu, Ching-Ti and Kelly, Tanika N and Evans, Michele K and Bouchard, Claude and Fox, Ervin R and Kooperberg, Charles and Zhu, Xiaofeng and Lakka, Timo A and Esko, T{\~o}nu and North, Kari E and Deary, Ian J and Snieder, Harold and Penninx, Brenda W J H and Gauderman, W James and Rao, Dabeeru C and Redline, Susan and van Heemst, Diana} } @article {8713, title = {A System for Phenotype Harmonization in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program.}, journal = {Am J Epidemiol}, year = {2021}, month = {2021 Apr 16}, abstract = {

Genotype-phenotype association studies often combine phenotype data from multiple studies to increase power. Harmonization of the data usually requires substantial effort due to heterogeneity in phenotype definitions, study design, data collection procedures, and data set organization. Here we describe a centralized system for phenotype harmonization that includes input from phenotype domain and study experts, quality control, documentation, reproducible results, and data sharing mechanisms. This system was developed for the National Heart, Lung and Blood Institute{\textquoteright}s Trans-Omics for Precision Medicine program, which is generating genomic and other omics data for >80 studies with extensive phenotype data. To date, 63 phenotypes have been harmonized across thousands of participants from up to 17 studies per phenotype (participants recruited 1948-2012). We discuss challenges in this undertaking and how they were addressed. The harmonized phenotype data and associated documentation have been submitted to National Institutes of Health data repositories for controlled-access by the scientific community. We also provide materials to facilitate future harmonization efforts by the community, which include (1) the code used to generate the 63 harmonized phenotypes, enabling others to reproduce, modify or extend these harmonizations to additional studies; and (2) results of labeling thousands of phenotype variables with controlled vocabulary terms.

}, issn = {1476-6256}, doi = {10.1093/aje/kwab115}, author = {Stilp, Adrienne M and Emery, Leslie S and Broome, Jai G and Buth, Erin J and Khan, Alyna T and Laurie, Cecelia A and Wang, Fei Fei and Wong, Quenna and Chen, Dongquan and D{\textquoteright}Augustine, Catherine M and Heard-Costa, Nancy L and Hohensee, Chancellor R and Johnson, William Craig and Juarez, Lucia D and Liu, Jingmin and Mutalik, Karen M and Raffield, Laura M and Wiggins, Kerri L and de Vries, Paul S and Kelly, Tanika N and Kooperberg, Charles and Natarajan, Pradeep and Peloso, Gina M and Peyser, Patricia A and Reiner, Alex P and Arnett, Donna K and Aslibekyan, Stella and Barnes, Kathleen C and Bielak, Lawrence F and Bis, Joshua C and Cade, Brian E and Chen, Ming-Huei and Correa, Adolfo and Cupples, L Adrienne and de Andrade, Mariza and Ellinor, Patrick T and Fornage, Myriam and Franceschini, Nora and Gan, Weiniu and Ganesh, Santhi K and Graffelman, Jan and Grove, Megan L and Guo, Xiuqing and Hawley, Nicola L and Hsu, Wan-Ling and Jackson, Rebecca D and Jaquish, Cashell E and Johnson, Andrew D and Kardia, Sharon L R and Kelly, Shannon and Lee, Jiwon and Mathias, Rasika A and McGarvey, Stephen T and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and North, Kari E and Nouraie, Seyed Mehdi and Oelsner, Elizabeth C and Pankratz, Nathan and Rich, Stephen S and Rotter, Jerome I and Smith, Jennifer A and Taylor, Kent D and Vasan, Ramachandran S and Weeks, Daniel E and Weiss, Scott T and Wilson, Carla G and Yanek, Lisa R and Psaty, Bruce M and Heckbert, Susan R and Laurie, Cathy C} } @article {8779, title = {Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 05 06}, pages = {874-893}, abstract = {

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3~bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 16, Datasets as Topic, Erythrocytes, Female, Gene Editing, Genetic Variation, Genome-Wide Association Study, HEK293 Cells, Humans, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Quality Control, Reproducibility of Results, United States}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.04.003}, author = {Hu, Yao and Stilp, Adrienne M and McHugh, Caitlin P and Rao, Shuquan and Jain, Deepti and Zheng, Xiuwen and Lane, John and M{\'e}ric de Bellefon, S{\'e}bastian and Raffield, Laura M and Chen, Ming-Huei and Yanek, Lisa R and Wheeler, Marsha and Yao, Yao and Ren, Chunyan and Broome, Jai and Moon, Jee-Young and de Vries, Paul S and Hobbs, Brian D and Sun, Quan and Surendran, Praveen and Brody, Jennifer A and Blackwell, Thomas W and Choquet, Helene and Ryan, Kathleen and Duggirala, Ravindranath and Heard-Costa, Nancy and Wang, Zhe and Chami, Nathalie and Preuss, Michael H and Min, Nancy and Ekunwe, Lynette and Lange, Leslie A and Cushman, Mary and Faraday, Nauder and Curran, Joanne E and Almasy, Laura and Kundu, Kousik and Smith, Albert V and Gabriel, Stacey and Rotter, Jerome I and Fornage, Myriam and Lloyd-Jones, Donald M and Vasan, Ramachandran S and Smith, Nicholas L and North, Kari E and Boerwinkle, Eric and Becker, Lewis C and Lewis, Joshua P and Abecasis, Goncalo R and Hou, Lifang and O{\textquoteright}Connell, Jeffrey R and Morrison, Alanna C and Beaty, Terri H and Kaplan, Robert and Correa, Adolfo and Blangero, John and Jorgenson, Eric and Psaty, Bruce M and Kooperberg, Charles and Walton, Russell T and Kleinstiver, Benjamin P and Tang, Hua and Loos, Ruth J F and Soranzo, Nicole and Butterworth, Adam S and Nickerson, Debbie and Rich, Stephen S and Mitchell, Braxton D and Johnson, Andrew D and Auer, Paul L and Li, Yun and Mathias, Rasika A and Lettre, Guillaume and Pankratz, Nathan and Laurie, Cathy C and Laurie, Cecelia A and Bauer, Daniel E and Conomos, Matthew P and Reiner, Alexander P} } @article {8914, title = {Whole-genome sequencing in diverse subjects identifies genetic correlates of leukocyte traits: The NHLBI TOPMed program.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 10 07}, pages = {1836-1851}, abstract = {

Many common and rare variants associated with hematologic traits have been discovered through imputation on large-scale reference panels. However, the majority of genome-wide association studies (GWASs) have been conducted in Europeans, and determining causal variants has proved challenging. We performed a GWAS of total leukocyte, neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts generated from 109,563,748 variants in the autosomes and the X chromosome in the Trans-Omics for Precision Medicine (TOPMed) program, which included data from 61,802 individuals of diverse ancestry. We discovered and replicated 7 leukocyte trait associations, including (1) the association between a chromosome X, pseudo-autosomal region (PAR), noncoding variant located between cytokine receptor genes (CSF2RA and CLRF2) and lower eosinophil count; and (2) associations between single variants found predominantly among African Americans at the S1PR3 (9q22.1) and HBB (11p15.4) loci and monocyte and lymphocyte counts, respectively. We further provide evidence indicating that the newly discovered eosinophil-lowering chromosome X PAR variant might be associated with reduced susceptibility to common allergic diseases such as atopic dermatitis and asthma. Additionally, we found a burden of very rare FLT3 (13q12.2) variants associated with monocyte counts. Together, these results emphasize the utility of whole-genome sequencing in diverse samples in identifying associations missed by European-ancestry-driven GWASs.

}, keywords = {Asthma, Biomarkers, Dermatitis, Atopic, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Leukocytes, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Polymorphism, Single Nucleotide, Prognosis, Proteome, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, United Kingdom, United States, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.08.007}, author = {Mikhaylova, Anna V and McHugh, Caitlin P and Polfus, Linda M and Raffield, Laura M and Boorgula, Meher Preethi and Blackwell, Thomas W and Brody, Jennifer A and Broome, Jai and Chami, Nathalie and Chen, Ming-Huei and Conomos, Matthew P and Cox, Corey and Curran, Joanne E and Daya, Michelle and Ekunwe, Lynette and Glahn, David C and Heard-Costa, Nancy and Highland, Heather M and Hobbs, Brian D and Ilboudo, Yann and Jain, Deepti and Lange, Leslie A and Miller-Fleming, Tyne W and Min, Nancy and Moon, Jee-Young and Preuss, Michael H and Rosen, Jonathon and Ryan, Kathleen and Smith, Albert V and Sun, Quan and Surendran, Praveen and de Vries, Paul S and Walter, Klaudia and Wang, Zhe and Wheeler, Marsha and Yanek, Lisa R and Zhong, Xue and Abecasis, Goncalo R and Almasy, Laura and Barnes, Kathleen C and Beaty, Terri H and Becker, Lewis C and Blangero, John and Boerwinkle, Eric and Butterworth, Adam S and Chavan, Sameer and Cho, Michael H and Choquet, Helene and Correa, Adolfo and Cox, Nancy and DeMeo, Dawn L and Faraday, Nauder and Fornage, Myriam and Gerszten, Robert E and Hou, Lifang and Johnson, Andrew D and Jorgenson, Eric and Kaplan, Robert and Kooperberg, Charles and Kundu, Kousik and Laurie, Cecelia A and Lettre, Guillaume and Lewis, Joshua P and Li, Bingshan and Li, Yun and Lloyd-Jones, Donald M and Loos, Ruth J F and Manichaikul, Ani and Meyers, Deborah A and Mitchell, Braxton D and Morrison, Alanna C and Ngo, Debby and Nickerson, Deborah A and Nongmaithem, Suraj and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Ortega, Victor E and Pankratz, Nathan and Perry, James A and Psaty, Bruce M and Rich, Stephen S and Soranzo, Nicole and Rotter, Jerome I and Silverman, Edwin K and Smith, Nicholas L and Tang, Hua and Tracy, Russell P and Thornton, Timothy A and Vasan, Ramachandran S and Zein, Joe and Mathias, Rasika A and Reiner, Alexander P and Auer, Paul L} } @article {9246, title = {Correlations between complex human phenotypes vary by genetic background, gender, and environment.}, journal = {Cell Rep Med}, volume = {3}, year = {2022}, month = {2022 Dec 20}, pages = {100844}, abstract = {

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet \~{}20{\texttimes} faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we introduce "fractional genetic correlation" as the fraction of phenotypic correlation explained by genetics. Finally, we quantify the enrichment of correlations between phenotypic domains, each of which is comprised of multiple phenotypes. Altogether, we demonstrate that the observed correlations between complex human phenotypes depend on the genetic background of the individuals, their gender, and their environment.

}, keywords = {Female, Genetic Background, Humans, Male, Phenotype}, issn = {2666-3791}, doi = {10.1016/j.xcrm.2022.100844}, author = {Elgart, Michael and Goodman, Matthew O and Isasi, Carmen and Chen, Han and Morrison, Alanna C and de Vries, Paul S and Xu, Huichun and Manichaikul, Ani W and Guo, Xiuqing and Franceschini, Nora and Psaty, Bruce M and Rich, Stephen S and Rotter, Jerome I and Lloyd-Jones, Donald M and Fornage, Myriam and Correa, Adolfo and Heard-Costa, Nancy L and Vasan, Ramachandran S and Hernandez, Ryan and Kaplan, Robert C and Redline, Susan and Sofer, Tamar} } @article {9194, title = {Cross-Ancestry Investigation of Venous Thromboembolism Genomic Predictors.}, journal = {Circulation}, volume = {146}, year = {2022}, month = {2022 Oct 18}, pages = {1225-1242}, abstract = {

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.

METHODS: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.

RESULTS: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1\% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.

CONCLUSIONS: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

}, keywords = {Genetic Predisposition to Disease, Genome-Wide Association Study, Genomics, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Thrombosis, Venous Thromboembolism}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.122.059675}, author = {Thibord, Florian and Klarin, Derek and Brody, Jennifer A and Chen, Ming-Huei and Levin, Michael G and Chasman, Daniel I and Goode, Ellen L and Hveem, Kristian and Teder-Laving, Maris and Martinez-Perez, Angel and A{\"\i}ssi, Dylan and Daian-Bacq, Delphine and Ito, Kaoru and Natarajan, Pradeep and Lutsey, Pamela L and Nadkarni, Girish N and de Vries, Paul S and Cuellar-Partida, Gabriel and Wolford, Brooke N and Pattee, Jack W and Kooperberg, Charles and Braekkan, Sigrid K and Li-Gao, Ruifang and Saut, No{\'e}mie and Sept, Corriene and Germain, Marine and Judy, Renae L and Wiggins, Kerri L and Ko, Darae and O{\textquoteright}Donnell, Christopher J and Taylor, Kent D and Giulianini, Franco and de Andrade, Mariza and N{\o}st, Therese H and Boland, Anne and Empana, Jean-Philippe and Koyama, Satoshi and Gilliland, Thomas and Do, Ron and Huffman, Jennifer E and Wang, Xin and Zhou, Wei and Manuel Soria, Jose and Carlos Souto, Juan and Pankratz, Nathan and Haessler, Jeffery and Hindberg, Kristian and Rosendaal, Frits R and Turman, Constance and Olaso, Robert and Kember, Rachel L and Bartz, Traci M and Lynch, Julie A and Heckbert, Susan R and Armasu, Sebastian M and Brumpton, Ben and Smadja, David M and Jouven, Xavier and Komuro, Issei and Clapham, Katharine R and Loos, Ruth J F and Willer, Cristen J and Sabater-Lleal, Maria and Pankow, James S and Reiner, Alexander P and Morelli, Vania M and Ridker, Paul M and Vlieg, Astrid van Hylckama and Deleuze, Jean-Francois and Kraft, Peter and Rader, Daniel J and Min Lee, Kyung and Psaty, Bruce M and Heidi Skogholt, Anne and Emmerich, Joseph and Suchon, Pierre and Rich, Stephen S and Vy, Ha My T and Tang, Weihong and Jackson, Rebecca D and Hansen, John-Bjarne and Morange, Pierre-Emmanuel and Kabrhel, Christopher and Tr{\'e}gou{\"e}t, David-Alexandre and Damrauer, Scott M and Johnson, Andrew D and Smith, Nicholas L} } @article {9253, title = {A framework for detecting noncoding rare-variant associations of large-scale whole-genome sequencing studies.}, journal = {Nat Methods}, volume = {19}, year = {2022}, month = {2022 Dec}, pages = {1599-1611}, abstract = {

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate multiple functional annotations. In non-gene-centric analysis, STAARpipeline uses SCANG-STAAR to incorporate dynamic window sizes and multiple functional annotations. We apply STAARpipeline to identify noncoding RV sets associated with four lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several of them in an additional 9,123 TOPMed samples. We also analyze five non-lipid TOPMed traits.

}, keywords = {Genetic Variation, Genome, Genome-Wide Association Study, Humans, Phenotype, Whole Genome Sequencing}, issn = {1548-7105}, doi = {10.1038/s41592-022-01640-x}, author = {Li, Zilin and Li, Xihao and Zhou, Hufeng and Gaynor, Sheila M and Selvaraj, Margaret Sunitha and Arapoglou, Theodore and Quick, Corbin and Liu, Yaowu and Chen, Han and Sun, Ryan and Dey, Rounak and Arnett, Donna K and Auer, Paul L and Bielak, Lawrence F and Bis, Joshua C and Blackwell, Thomas W and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Conomos, Matthew P and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and de Vries, Paul S and Duggirala, Ravindranath and Franceschini, Nora and Freedman, Barry I and G{\"o}ring, Harald H H and Guo, Xiuqing and Kalyani, Rita R and Kooperberg, Charles and Kral, Brian G and Lange, Leslie A and Lin, Bridget M and Manichaikul, Ani and Manning, Alisa K and Martin, Lisa W and Mathias, Rasika A and Meigs, James B and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Rice, Kenneth M and Rich, Stephen S and Smith, Jennifer A and Taylor, Kent D and Taub, Margaret A and Vasan, Ramachandran S and Weeks, Daniel E and Wilson, James G and Yanek, Lisa R and Zhao, Wei and Rotter, Jerome I and Willer, Cristen J and Natarajan, Pradeep and Peloso, Gina M and Lin, Xihong} } @article {9099, title = {Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.}, journal = {Hypertension}, year = {2022}, month = {2022 Jun 02}, pages = {101161HYPERTENSIONAHA12219324}, abstract = {

BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.

METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants.

RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (<5{\texttimes}10). Among them, a rare intergenic variant at novel locus, , was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; =4.99{\texttimes}10) but not stage-2 analysis (=0.11). Furthermore, a novel common variant at the known locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; =4.18{\texttimes}10) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; =7.28{\texttimes}10). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (<1{\texttimes}10 and <1{\texttimes}10, respectively).

DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

}, issn = {1524-4563}, doi = {10.1161/HYPERTENSIONAHA.122.19324}, author = {Kelly, Tanika N and Sun, Xiao and He, Karen Y and Brown, Michael R and Taliun, Sarah A Gagliano and Hellwege, Jacklyn N and Irvin, Marguerite R and Mi, Xuenan and Brody, Jennifer A and Franceschini, Nora and Guo, Xiuqing and Hwang, Shih-Jen and de Vries, Paul S and Gao, Yan and Moscati, Arden and Nadkarni, Girish N and Yanek, Lisa R and Elfassy, Tali and Smith, Jennifer A and Chung, Ren-Hua and Beitelshees, Amber L and Patki, Amit and Aslibekyan, Stella and Blobner, Brandon M and Peralta, Juan M and Assimes, Themistocles L and Palmas, Walter R and Liu, Chunyu and Bress, Adam P and Huang, Zhijie and Becker, Lewis C and Hwa, Chii-Min and O{\textquoteright}Connell, Jeffrey R and Carlson, Jenna C and Warren, Helen R and Das, Sayantan and Giri, Ayush and Martin, Lisa W and Craig Johnson, W and Fox, Ervin R and Bottinger, Erwin P and Razavi, Alexander C and Vaidya, Dhananjay and Chuang, Lee-Ming and Chang, Yen-Pei C and Naseri, Take and Jain, Deepti and Kang, Hyun Min and Hung, Adriana M and Srinivasasainagendra, Vinodh and Snively, Beverly M and Gu, Dongfeng and Montasser, May E and Reupena, Muagututi{\textquoteright}a Sefuiva and Heavner, Benjamin D and LeFaive, Jonathon and Hixson, James E and Rice, Kenneth M and Wang, Fei Fei and Nielsen, Jonas B and Huang, Jianfeng and Khan, Alyna T and Zhou, Wei and Nierenberg, Jovia L and Laurie, Cathy C and Armstrong, Nicole D and Shi, Mengyao and Pan, Yang and Stilp, Adrienne M and Emery, Leslie and Wong, Quenna and Hawley, Nicola L and Minster, Ryan L and Curran, Joanne E and Munroe, Patricia B and Weeks, Daniel E and North, Kari E and Tracy, Russell P and Kenny, Eimear E and Shimbo, Daichi and Chakravarti, Aravinda and Rich, Stephen S and Reiner, Alex P and Blangero, John and Redline, Susan and Mitchell, Braxton D and Rao, Dabeeru C and Ida Chen, Yii-Der and Kardia, Sharon L R and Kaplan, Robert C and Mathias, Rasika A and He, Jiang and Psaty, Bruce M and Fornage, Myriam and Loos, Ruth J F and Correa, Adolfo and Boerwinkle, Eric and Rotter, Jerome I and Kooperberg, Charles and Edwards, Todd L and Abecasis, Goncalo R and Zhu, Xiaofeng and Levy, Daniel and Arnett, Donna K and Morrison, Alanna C} } @article {8975, title = {Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.}, journal = {Am J Hum Genet}, volume = {109}, year = {2022}, month = {2022 01 06}, pages = {81-96}, abstract = {

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1\%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

}, keywords = {Alleles, Blood Glucose, Case-Control Studies, Computational Biology, Databases, Genetic, Diabetes Mellitus, Type 2, Exome, Genetic Predisposition to Disease, Genetic Variation, Genetics, Population, Genome-Wide Association Study, Humans, Lipid Metabolism, Lipids, Liver, Molecular Sequence Annotation, Multifactorial Inheritance, Open Reading Frames, Phenotype, Polymorphism, Single Nucleotide}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.11.021}, author = {Hindy, George and Dornbos, Peter and Chaffin, Mark D and Liu, Dajiang J and Wang, Minxian and Selvaraj, Margaret Sunitha and Zhang, David and Park, Joseph and Aguilar-Salinas, Carlos A and Antonacci-Fulton, Lucinda and Ardissino, Diego and Arnett, Donna K and Aslibekyan, Stella and Atzmon, Gil and Ballantyne, Christie M and Barajas-Olmos, Francisco and Barzilai, Nir and Becker, Lewis C and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bonnycastle, Lori L and Bottinger, Erwin and Bowden, Donald W and Bown, Matthew J and Brody, Jennifer A and Broome, Jai G and Burtt, Noel P and Cade, Brian E and Centeno-Cruz, Federico and Chan, Edmund and Chang, Yi-Cheng and Chen, Yii-der I and Cheng, Ching-Yu and Choi, Won Jung and Chowdhury, Rajiv and Contreras-Cubas, Cecilia and C{\'o}rdova, Emilio J and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Danesh, John and de Vries, Paul S and DeFronzo, Ralph A and Doddapaneni, Harsha and Duggirala, Ravindranath and Dutcher, Susan K and Ellinor, Patrick T and Emery, Leslie S and Florez, Jose C and Fornage, Myriam and Freedman, Barry I and Fuster, Valentin and Garay-Sevilla, Ma Eugenia and Garc{\'\i}a-Ortiz, Humberto and Germer, Soren and Gibbs, Richard A and Gieger, Christian and Glaser, Benjamin and Gonzalez, Clicerio and Gonzalez-Villalpando, Maria Elena and Graff, Mariaelisa and Graham, Sarah E and Grarup, Niels and Groop, Leif C and Guo, Xiuqing and Gupta, Namrata and Han, Sohee and Hanis, Craig L and Hansen, Torben and He, Jiang and Heard-Costa, Nancy L and Hung, Yi-Jen and Hwang, Mi Yeong and Irvin, Marguerite R and Islas-Andrade, Sergio and Jarvik, Gail P and Kang, Hyun Min and Kardia, Sharon L R and Kelly, Tanika and Kenny, Eimear E and Khan, Alyna T and Kim, Bong-Jo and Kim, Ryan W and Kim, Young Jin and Koistinen, Heikki A and Kooperberg, Charles and Kuusisto, Johanna and Kwak, Soo Heon and Laakso, Markku and Lange, Leslie A and Lee, Jiwon and Lee, Juyoung and Lee, Seonwook and Lehman, Donna M and Lemaitre, Rozenn N and Linneberg, Allan and Liu, Jianjun and Loos, Ruth J F and Lubitz, Steven A and Lyssenko, Valeriya and Ma, Ronald C W and Martin, Lisa Warsinger and Mart{\'\i}nez-Hern{\'a}ndez, Ang{\'e}lica and Mathias, Rasika A and McGarvey, Stephen T and McPherson, Ruth and Meigs, James B and Meitinger, Thomas and Melander, Olle and Mendoza-Caamal, Elvia and Metcalf, Ginger A and Mi, Xuenan and Mohlke, Karen L and Montasser, May E and Moon, Jee-Young and Moreno-Macias, Hortensia and Morrison, Alanna C and Muzny, Donna M and Nelson, Sarah C and Nilsson, Peter M and O{\textquoteright}Connell, Jeffrey R and Orho-Melander, Marju and Orozco, Lorena and Palmer, Colin N A and Palmer, Nicholette D and Park, Cheol Joo and Park, Kyong Soo and Pedersen, Oluf and Peralta, Juan M and Peyser, Patricia A and Post, Wendy S and Preuss, Michael and Psaty, Bruce M and Qi, Qibin and Rao, D C and Redline, Susan and Reiner, Alexander P and Revilla-Monsalve, Cristina and Rich, Stephen S and Samani, Nilesh and Schunkert, Heribert and Schurmann, Claudia and Seo, Daekwan and Seo, Jeong-Sun and Sim, Xueling and Sladek, Rob and Small, Kerrin S and So, Wing Yee and Stilp, Adrienne M and Tai, E Shyong and Tam, Claudia H T and Taylor, Kent D and Teo, Yik Ying and Thameem, Farook and Tomlinson, Brian and Tsai, Michael Y and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and van Dam, Rob M and Vasan, Ramachandran S and Viaud Martinez, Karine A and Wang, Fei Fei and Wang, Xuzhi and Watkins, Hugh and Weeks, Daniel E and Wilson, James G and Witte, Daniel R and Wong, Tien-Yin and Yanek, Lisa R and Kathiresan, Sekar and Rader, Daniel J and Rotter, Jerome I and Boehnke, Michael and McCarthy, Mark I and Willer, Cristen J and Natarajan, Pradeep and Flannick, Jason A and Khera, Amit V and Peloso, Gina M} } @article {9158, title = {Whole genome sequence association analysis of fasting glucose and fasting insulin levels in diverse cohorts from the NHLBI TOPMed program.}, journal = {Commun Biol}, volume = {5}, year = {2022}, month = {2022 07 28}, pages = {756}, abstract = {

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{\textquoteright}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.

}, keywords = {Diabetes Mellitus, Type 2, Fasting, Glucose, Humans, Insulin, National Heart, Lung, and Blood Institute (U.S.), Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Precision Medicine, Receptors, Immunologic, United States}, issn = {2399-3642}, doi = {10.1038/s42003-022-03702-4}, author = {DiCorpo, Daniel and Gaynor, Sheila M and Russell, Emily M and Westerman, Kenneth E and Raffield, Laura M and Majarian, Timothy D and Wu, Peitao and Sarnowski, Chloe and Highland, Heather M and Jackson, Anne and Hasbani, Natalie R and de Vries, Paul S and Brody, Jennifer A and Hidalgo, Bertha and Guo, Xiuqing and Perry, James A and O{\textquoteright}Connell, Jeffrey R and Lent, Samantha and Montasser, May E and Cade, Brian E and Jain, Deepti and Wang, Heming and D{\textquoteright}Oliveira Albanus, Ricardo and Varshney, Arushi and Yanek, Lisa R and Lange, Leslie and Palmer, Nicholette D and Almeida, Marcio and Peralta, Juan M and Aslibekyan, Stella and Baldridge, Abigail S and Bertoni, Alain G and Bielak, Lawrence F and Chen, Chung-Shiuan and Chen, Yii-Der Ida and Choi, Won Jung and Goodarzi, Mark O and Floyd, James S and Irvin, Marguerite R and Kalyani, Rita R and Kelly, Tanika N and Lee, Seonwook and Liu, Ching-Ti and Loesch, Douglas and Manson, JoAnn E and Minster, Ryan L and Naseri, Take and Pankow, James S and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Selvin, Elizabeth and Smith, Jennifer A and Weeks, Daniel E and Xu, Huichun and Yao, Jie and Zhao, Wei and Parker, Stephen and Alonso, Alvaro and Arnett, Donna K and Blangero, John and Boerwinkle, Eric and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and Duggirala, Ravindranath and He, Jiang and Heckbert, Susan R and Kardia, Sharon L R and Kim, Ryan W and Kooperberg, Charles and Liu, Simin and Mathias, Rasika A and McGarvey, Stephen T and Mitchell, Braxton D and Morrison, Alanna C and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Shuldiner, Alan R and Taylor, Kent D and Vasan, Ramachandran S and Viaud-Martinez, Karine A and Florez, Jose C and Wilson, James G and Sladek, Robert and Rich, Stephen S and Rotter, Jerome I and Lin, Xihong and Dupuis, Jos{\'e}e and Meigs, James B and Wessel, Jennifer and Manning, Alisa K} } @article {9261, title = {Whole genome sequencing identifies structural variants contributing to hematologic traits in the NHLBI TOPMed program.}, journal = {Nat Commun}, volume = {13}, year = {2022}, month = {2022 Dec 08}, pages = {7592}, abstract = {

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.

}, keywords = {Blood Cells, Genome-Wide Association Study, Humans, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-022-35354-7}, author = {Wheeler, Marsha M and Stilp, Adrienne M and Rao, Shuquan and Halldorsson, Bjarni V and Beyter, Doruk and Wen, Jia and Mihkaylova, Anna V and McHugh, Caitlin P and Lane, John and Jiang, Min-Zhi and Raffield, Laura M and Jun, Goo and Sedlazeck, Fritz J and Metcalf, Ginger and Yao, Yao and Bis, Joshua B and Chami, Nathalie and de Vries, Paul S and Desai, Pinkal and Floyd, James S and Gao, Yan and Kammers, Kai and Kim, Wonji and Moon, Jee-Young and Ratan, Aakrosh and Yanek, Lisa R and Almasy, Laura and Becker, Lewis C and Blangero, John and Cho, Michael H and Curran, Joanne E and Fornage, Myriam and Kaplan, Robert C and Lewis, Joshua P and Loos, Ruth J F and Mitchell, Braxton D and Morrison, Alanna C and Preuss, Michael and Psaty, Bruce M and Rich, Stephen S and Rotter, Jerome I and Tang, Hua and Tracy, Russell P and Boerwinkle, Eric and Abecasis, Goncalo R and Blackwell, Thomas W and Smith, Albert V and Johnson, Andrew D and Mathias, Rasika A and Nickerson, Deborah A and Conomos, Matthew P and Li, Yun and {\TH}orsteinsdottir, Unnur and Magn{\'u}sson, Magn{\'u}s K and Stefansson, Kari and Pankratz, Nathan D and Bauer, Daniel E and Auer, Paul L and Reiner, Alex P} } @article {9708, title = {Antithrombin, Protein C, and Protein S: Genome and Transcriptome-Wide Association Studies Identify 7 Novel Loci Regulating Plasma Levels.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {43}, year = {2023}, month = {2023 Jul}, pages = {e254-e269}, abstract = {

BACKGROUND: Antithrombin, PC (protein C), and PS (protein S) are circulating natural anticoagulant proteins that regulate hemostasis and of which partial deficiencies are causes of venous thromboembolism. Previous genetic association studies involving antithrombin, PC, and PS were limited by modest sample sizes or by being restricted to candidate genes. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, we meta-analyzed across ancestries the results from 10 genome-wide association studies of plasma levels of antithrombin, PC, PS free, and PS total.

METHODS: Study participants were of European and African ancestries, and genotype data were imputed to TOPMed, a dense multiancestry reference panel. Each of the 10 studies conducted a genome-wide association studies for each phenotype and summary results were meta-analyzed, stratified by ancestry. Analysis of antithrombin included 25 243 European ancestry and 2688 African ancestry participants, PC analysis included 16 597 European ancestry and 2688 African ancestry participants, PSF and PST analysis included 4113 and 6409 European ancestry participants. We also conducted transcriptome-wide association analyses and multiphenotype analysis to discover additional associations. Novel genome-wide association studies and transcriptome-wide association analyses findings were validated by in vitro functional experiments. Mendelian randomization was performed to assess the causal relationship between these proteins and cardiovascular outcomes.

RESULTS: Genome-wide association studies meta-analyses identified 4 newly associated loci: 3 with antithrombin levels (, , and ) and 1 with PS levels (-). transcriptome-wide association analyses identified 3 newly associated genes: 1 with antithrombin level (), 1 with PC (), and 1 with PS (). In addition, we replicated 7 independent loci reported in previous studies. Functional experiments provided evidence for the involvement of , , and genes in antithrombin regulation.

CONCLUSIONS: The use of larger sample sizes, diverse populations, and a denser imputation reference panel allowed the detection of 7 novel genomic loci associated with plasma antithrombin, PC, and PS levels.

}, keywords = {Anticoagulants, Antithrombin III, Antithrombins, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Protein C, Protein S, Transcriptome}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.122.318213}, author = {Ji, Yuekai and Temprano-Sagrera, Gerard and Holle, Lori A and Bebo, Allison and Brody, Jennifer A and Le, Ngoc-Quynh and Kangro, Kadri and Brown, Michael R and Martinez-Perez, Angel and Sitlani, Colleen M and Suchon, Pierre and Kleber, Marcus E and Emmert, David B and Bilge Ozel, Ayse and Dobson, Dre{\textquoteright}Von A and Tang, Weihong and Llobet, Dolors and Tracy, Russell P and Deleuze, Jean-Francois and Delgado, Graciela E and G{\"o}gele, Martin and Wiggins, Kerri L and Souto, Juan Carlos and Pankow, James S and Taylor, Kent D and Tr{\'e}gou{\"e}t, David-Alexandre and Moissl, Angela P and Fuchsberger, Christian and Rosendaal, Frits R and Morrison, Alanna C and Soria, Jos{\'e} Manuel and Cushman, Mary and Morange, Pierre-Emmanuel and M{\"a}rz, Winfried and Hicks, Andrew A and Desch, Karl C and Johnson, Andrew D and de Vries, Paul S and Wolberg, Alisa S and Smith, Nicholas L and Sabater-Lleal, Maria} } @article {9285, title = {Association of Rare Protein-Truncating DNA Variants in APOB or PCSK9 With Low-density Lipoprotein Cholesterol Level and Risk of Coronary Heart Disease.}, journal = {JAMA Cardiol}, year = {2023}, month = {2023 Feb 01}, abstract = {

IMPORTANCE: Protein-truncating variants (PTVs) in apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with significantly lower low-density lipoprotein (LDL) cholesterol concentrations. The association of these PTVs with coronary heart disease (CHD) warrants further characterization in large, multiracial prospective cohort studies.

OBJECTIVE: To evaluate the association of PTVs in APOB and PCSK9 with LDL cholesterol concentrations and CHD risk.

DESIGN, SETTING, AND PARTICIPANTS: This studied included participants from 5 National Heart, Lung, and Blood Institute (NHLBI) studies and the UK Biobank. NHLBI study participants aged 5 to 84 years were recruited between 1971 and 2002 across the US and underwent whole-genome sequencing. UK Biobank participants aged 40 to 69 years were recruited between 2006 and 2010 in the UK and underwent whole-exome sequencing. Data were analyzed from June 2021 to October 2022.

EXPOSURES: PTVs in APOB and PCSK9.

MAIN OUTCOMES AND MEASURES: Estimated untreated LDL cholesterol levels and CHD.

RESULTS: Among 19 073 NHLBI participants (10 598 [55.6\%] female; mean [SD] age, 52 [17] years), 139 (0.7\%) carried an APOB or PCSK9 PTV, which was associated with 49 mg/dL (95\% CI, 43-56) lower estimated untreated LDL cholesterol level. Over a median (IQR) follow-up of 21.5 (13.9-29.4) years, incident CHD was observed in 12 of 139 carriers (8.6\%) vs 3029 of 18 934 noncarriers (16.0\%), corresponding to an adjusted hazard ratio of 0.51 (95\% CI, 0.28-0.89; P = .02). Among 190 464 UK Biobank participants (104 831 [55.0\%] female; mean [SD] age, 57 [8] years), 662 (0.4\%) carried a PTV, which was associated with 45 mg/dL (95\% CI, 42-47) lower estimated untreated LDL cholesterol level. Estimated CHD risk by age 75 years was 3.7\% (95\% CI, 2.0-5.3) in carriers vs 7.0\% (95\% CI, 6.9-7.2) in noncarriers, corresponding to an adjusted hazard ratio of 0.51 (95\% CI, 0.32-0.81; P = .004).

CONCLUSIONS AND RELEVANCE: Among 209 537 individuals in this study, 0.4\% carried an APOB or PCSK9 PTV that was associated with less exposure to LDL cholesterol and a 49\% lower risk of CHD.

}, issn = {2380-6591}, doi = {10.1001/jamacardio.2022.5271}, author = {Dron, Jacqueline S and Patel, Aniruddh P and Zhang, Yiyi and Jurgens, Sean J and Maamari, Dimitri J and Wang, Minxian and Boerwinkle, Eric and Morrison, Alanna C and de Vries, Paul S and Fornage, Myriam and Hou, Lifang and Lloyd-Jones, Donald M and Psaty, Bruce M and Tracy, Russell P and Bis, Joshua C and Vasan, Ramachandran S and Levy, Daniel and Heard-Costa, Nancy and Rich, Stephen S and Guo, Xiuqing and Taylor, Kent D and Gibbs, Richard A and Rotter, Jerome I and Willer, Cristen J and Oelsner, Elizabeth C and Moran, Andrew E and Peloso, Gina M and Natarajan, Pradeep and Khera, Amit V} } @article {9479, title = {Carriers of rare damaging genetic variants are at lower risk of atherosclerotic disease.}, journal = {medRxiv}, year = {2023}, month = {2023 Aug 16}, abstract = {

BACKGROUND: The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease.

METHODS: In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated.

RESULTS: A total of 45 predicted LoF or damaging missense variants were identified in the gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14\%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (OR : 0.62 95\%CI: 0.39-0.96; OR : 0.64 95\%CI: 0.34-1.19; OR : 0.64 95\%CI: 0.45-0.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging variants.

CONCLUSIONS: Heterozygous carriers of damaging variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.

}, doi = {10.1101/2023.08.14.23294063}, author = {Georgakis, Marios K and Malik, Rainer and Hasbani, Natalie R and Shakt, Gabrielle and Morrison, Alanna C and Tsao, Noah L and Judy, Renae and Mitchell, Braxton D and Xu, Huichun and Montasser, May E and Do, Ron and Kenny, Eimear E and Loos, Ruth J F and Terry, James G and Carr, John Jeffrey and Bis, Joshua C and Psaty, Bruce M and Longstreth, W T and Young, Kendra A and Lutz, Sharon M and Cho, Michael H and Broome, Jai and Khan, Alyna T and Wang, Fei Fei and Heard-Costa, Nancy and Seshadri, Sudha and Vasan, Ramachandran S and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Yanek, Lisa R and Kral, Brian G and Becker, Lewis C and Peyser, Patricia A and Bielak, Lawrence F and Ammous, Farah and Carson, April P and Hall, Michael E and Raffield, Laura M and Rich, Stephen S and Post, Wendy S and Tracy, Russel P and Taylor, Kent D and Guo, Xiuqing and Mahaney, Michael C and Curran, Joanne E and Blangero, John and Clarke, Shoa L and Haessler, Jeffrey W and Hu, Yao and Assimes, Themistocles L and Kooperberg, Charles and Damrauer, Scott M and Rotter, Jerome I and de Vries, Paul S and Dichgans, Martin} } @article {9535, title = {Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.}, journal = {Front Genet}, volume = {14}, year = {2023}, month = {2023}, pages = {1235337}, abstract = {

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 {\texttimes} 10) and suggestive ( < 1 {\texttimes} 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.

}, issn = {1664-8021}, doi = {10.3389/fgene.2023.1235337}, author = {de Las Fuentes, Lisa and Schwander, Karen L and Brown, Michael R and Bentley, Amy R and Winkler, Thomas W and Sung, Yun Ju and Munroe, Patricia B and Miller, Clint L and Aschard, Hugo and Aslibekyan, Stella and Bartz, Traci M and Bielak, Lawrence F and Chai, Jin Fang and Cheng, Ching-Yu and Dorajoo, Rajkumar and Feitosa, Mary F and Guo, Xiuqing and Hartwig, Fernando P and Horimoto, Andrea and Kolcic, Ivana and Lim, Elise and Liu, Yongmei and Manning, Alisa K and Marten, Jonathan and Musani, Solomon K and Noordam, Raymond and Padmanabhan, Sandosh and Rankinen, Tuomo and Richard, Melissa A and Ridker, Paul M and Smith, Albert V and Vojinovic, Dina and Zonderman, Alan B and Alver, Maris and Boissel, Mathilde and Christensen, Kaare and Freedman, Barry I and Gao, Chuan and Giulianini, Franco and Harris, Sarah E and He, Meian and Hsu, Fang-Chi and Kuhnel, Brigitte and Laguzzi, Federica and Li, Xiaoyin and Lyytik{\"a}inen, Leo-Pekka and Nolte, Ilja M and Poveda, Alaitz and Rauramaa, Rainer and Riaz, Muhammad and Robino, Antonietta and Sofer, Tamar and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Verweij, Niek and Ware, Erin B and Weiss, Stefan and Wen, Wanqing and Yanek, Lisa R and Zhan, Yiqiang and Amin, Najaf and Arking, Dan E and Ballantyne, Christie and Boerwinkle, Eric and Brody, Jennifer A and Broeckel, Ulrich and Campbell, Archie and Canouil, Micka{\"e}l and Chai, Xiaoran and Chen, Yii-Der Ida and Chen, Xu and Chitrala, Kumaraswamy Naidu and Concas, Maria Pina and de Faire, Ulf and de Mutsert, Ren{\'e}e and de Silva, H Janaka and de Vries, Paul S and Do, Ahn and Faul, Jessica D and Fisher, Virginia and Floyd, James S and Forrester, Terrence and Friedlander, Yechiel and Girotto, Giorgia and Gu, C Charles and Hallmans, G{\"o}ran and Heikkinen, Sami and Heng, Chew-Kiat and Homuth, Georg and Hunt, Steven and Ikram, M Arfan and Jacobs, David R and Kavousi, Maryam and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Komulainen, Pirjo and Langefeld, Carl D and Liang, Jingjing and Liu, Kiang and Liu, Jianjun and Lohman, Kurt and M{\"a}gi, Reedik and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Milaneschi, Yuri and Nauck, Matthias and Nelson, Christopher P and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Pereira, Alexandre C and Perls, Thomas and Peters, Annette and Polasek, Ozren and Raitakari, Olli T and Rice, Kenneth and Rice, Treva K and Rich, Stephen S and Sabanayagam, Charumathi and Schreiner, Pamela J and Shu, Xiao-Ou and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Starr, John M and Strauch, Konstantin and Tai, E Shyong and Taylor, Kent D and Tsai, Michael Y and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Waldenberger, Melanie and Wang, Ya-Xing and Wei, Wen-Bin and Wilson, Gregory and Xuan, Deng and Yao, Jie and Yu, Caizheng and Yuan, Jian-Min and Zhao, Wei and Becker, Diane M and Bonnefond, Am{\'e}lie and Bowden, Donald W and Cooper, Richard S and Deary, Ian J and Divers, Jasmin and Esko, T{\~o}nu and Franks, Paul W and Froguel, Philippe and Gieger, Christian and Jonas, Jost B and Kato, Norihiro and Lakka, Timo A and Leander, Karin and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and North, Kari E and Ntalla, Ioanna and Penninx, Brenda and Samani, Nilesh J and Snieder, Harold and Spedicati, Beatrice and van der Harst, Pim and V{\"o}lzke, Henry and Wagenknecht, Lynne E and Weir, David R and Wojczynski, Mary K and Wu, Tangchun and Zheng, Wei and Zhu, Xiaofeng and Bouchard, Claude and Chasman, Daniel I and Evans, Michele K and Fox, Ervin R and Gudnason, Vilmundur and Hayward, Caroline and Horta, Bernardo L and Kardia, Sharon L R and Krieger, Jose Eduardo and Mook-Kanamori, Dennis O and Peyser, Patricia A and Province, Michael M and Psaty, Bruce M and Rudan, Igor and Sim, Xueling and Smith, Blair H and van Dam, Rob M and van Duijn, Cornelia M and Wong, Tien Yin and Arnett, Donna K and Rao, Dabeeru C and Gauderman, James and Liu, Ching-Ti and Morrison, Alanna C and Rotter, Jerome I and Fornage, Myriam} } @article {9583, title = {Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.}, journal = {medRxiv}, year = {2023}, month = {2023 Nov 11}, abstract = {

OBJECTIVE: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP).

METHODS: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91\% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses.

RESULTS: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42{\textpm}0.09 mm Hg (P for interaction = 9.4e-7) and 0.20{\textpm}0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with -expression quantitative trait loci (eQTL) variants (P = 4e-273) and -DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is , the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene at 15q25.1.

CONCLUSION: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

}, doi = {10.1101/2023.11.10.23298402}, author = {Guirette, Melanie and Lan, Jessie and McKeown, Nicola and Brown, Michael R and Chen, Han and de Vries, Paul S and Kim, Hyunju and Rebholz, Casey M and Morrison, Alanna C and Bartz, Traci M and Fretts, Amanda M and Guo, Xiuqing and Lemaitre, Rozenn N and Liu, Ching-Ti and Noordam, Raymond and de Mutsert, Ren{\'e}e and Rosendaal, Frits R and Wang, Carol A and Beilin, Lawrence and Mori, Trevor A and Oddy, Wendy H and Pennell, Craig E and Chai, Jin Fang and Whitton, Clare and van Dam, Rob M and Liu, Jianjun and Tai, E Shyong and Sim, Xueling and Neuhouser, Marian L and Kooperberg, Charles and Tinker, Lesley and Franceschini, Nora and Huan, Tianxiao and Winkler, Thomas W and Bentley, Amy R and Gauderman, W James and Heerkens, Luc and Tanaka, Toshiko and van Rooij, Jeroen and Munroe, Patricia B and Warren, Helen R and Voortman, Trudy and Chen, Honglei and Rao, D C and Levy, Daniel and Ma, Jiantao} } @article {9501, title = {Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Oct}, pages = {1651-1664}, abstract = {

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

}, issn = {1546-1718}, doi = {10.1038/s41588-023-01518-4}, author = {Kavousi, Maryam and Bos, Maxime M and Barnes, Hanna J and Lino Cardenas, Christian L and Wong, Doris and Lu, Haojie and Hodonsky, Chani J and Landsmeer, Lennart P L and Turner, Adam W and Kho, Minjung and Hasbani, Natalie R and de Vries, Paul S and Bowden, Donald W and Chopade, Sandesh and Deelen, Joris and Benavente, Ernest Diez and Guo, Xiuqing and Hofer, Edith and Hwang, Shih-Jen and Lutz, Sharon M and Lyytik{\"a}inen, Leo-Pekka and Slenders, Lotte and Smith, Albert V and Stanislawski, Maggie A and van Setten, Jessica and Wong, Quenna and Yanek, Lisa R and Becker, Diane M and Beekman, Marian and Budoff, Matthew J and Feitosa, Mary F and Finan, Chris and Hilliard, Austin T and Kardia, Sharon L R and Kovacic, Jason C and Kral, Brian G and Langefeld, Carl D and Launer, Lenore J and Malik, Shaista and Hoesein, Firdaus A A Mohamed and Mokry, Michal and Schmidt, Reinhold and Smith, Jennifer A and Taylor, Kent D and Terry, James G and van der Grond, Jeroen and van Meurs, Joyce and Vliegenthart, Rozemarijn and Xu, Jianzhao and Young, Kendra A and Zilh{\~a}o, Nuno R and Zweiker, Robert and Assimes, Themistocles L and Becker, Lewis C and Bos, Daniel and Carr, J Jeffrey and Cupples, L Adrienne and de Kleijn, Dominique P V and de Winther, Menno and den Ruijter, Hester M and Fornage, Myriam and Freedman, Barry I and Gudnason, Vilmundur and Hingorani, Aroon D and Hokanson, John E and Ikram, M Arfan and I{\v s}gum, Ivana and Jacobs, David R and K{\"a}h{\"o}nen, Mika and Lange, Leslie A and Lehtim{\"a}ki, Terho and Pasterkamp, Gerard and Raitakari, Olli T and Schmidt, Helena and Slagboom, P Eline and Uitterlinden, Andr{\'e} G and Vernooij, Meike W and Bis, Joshua C and Franceschini, Nora and Psaty, Bruce M and Post, Wendy S and Rotter, Jerome I and Bj{\"o}rkegren, Johan L M and O{\textquoteright}Donnell, Christopher J and Bielak, Lawrence F and Peyser, Patricia A and Malhotra, Rajeev and van der Laan, Sander W and Miller, Clint L} } @article {9239, title = {Powerful, scalable and resource-efficient meta-analysis of rare variant associations in large whole genome sequencing studies.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Jan}, pages = {154-164}, abstract = {

Meta-analysis of whole genome sequencing/whole exome sequencing (WGS/WES) studies provides an attractive solution to the problem of collecting large sample sizes for discovering rare variants associated with complex phenotypes. Existing rare variant meta-analysis approaches are not scalable to biobank-scale WGS data. Here we present MetaSTAAR, a powerful and resource-efficient rare variant meta-analysis framework for large-scale WGS/WES studies. MetaSTAAR accounts for relatedness and population structure, can analyze both quantitative and dichotomous traits and boosts the power of rare variant tests by incorporating multiple variant functional annotations. Through meta-analysis of four lipid traits in 30,138 ancestrally diverse samples from 14 studies of the Trans Omics for Precision Medicine (TOPMed) Program, we show that MetaSTAAR performs rare variant meta-analysis at scale and produces results comparable to using pooled data. Additionally, we identified several conditionally significant rare variant associations with lipid traits. We further demonstrate that MetaSTAAR is scalable to biobank-scale cohorts through meta-analysis of TOPMed WGS data and UK Biobank WES data of ~200,000 samples.

}, keywords = {Exome Sequencing, Genome-Wide Association Study, Lipids, Phenotype, Whole Genome Sequencing}, issn = {1546-1718}, doi = {10.1038/s41588-022-01225-6}, author = {Li, Xihao and Quick, Corbin and Zhou, Hufeng and Gaynor, Sheila M and Liu, Yaowu and Chen, Han and Selvaraj, Margaret Sunitha and Sun, Ryan and Dey, Rounak and Arnett, Donna K and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Correa, Adolfo and Cupples, L Adrienne and Curran, Joanne E and de Vries, Paul S and Duggirala, Ravindranath and Freedman, Barry I and G{\"o}ring, Harald H H and Guo, Xiuqing and Haessler, Jeffrey and Kalyani, Rita R and Kooperberg, Charles and Kral, Brian G and Lange, Leslie A and Manichaikul, Ani and Martin, Lisa W and McGarvey, Stephen T and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Reupena, Muagututi{\textquoteright}a Sefuiva and Rice, Kenneth M and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Vasan, Ramachandran S and Willer, Cristen J and Wilson, James G and Yanek, Lisa R and Zhao, Wei and Rotter, Jerome I and Natarajan, Pradeep and Peloso, Gina M and Li, Zilin and Lin, Xihong} } @article {9418, title = {Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study.}, journal = {medRxiv}, year = {2023}, month = {2023 Jun 29}, abstract = {

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 {\textpm}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.

}, doi = {10.1101/2023.06.28.23291966}, author = {Wang, Yuxuan and Selvaraj, Margaret Sunitha and Li, Xihao and Li, Zilin and Holdcraft, Jacob A and Arnett, Donna K and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Cade, Brian E and Carlson, Jenna C and Carson, April P and Chen, Yii-Der Ida and Curran, Joanne E and de Vries, Paul S and Dutcher, Susan K and Ellinor, Patrick T and Floyd, James S and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Germer, Soren and Gibbs, Richard A and Guo, Xiuqing and He, Jiang and Heard-Costa, Nancy and Hildalgo, Bertha and Hou, Lifang and Irvin, Marguerite R and Joehanes, Roby and Kaplan, Robert C and Kardia, Sharon Lr and Kelly, Tanika N and Kim, Ryan and Kooperberg, Charles and Kral, Brian G and Levy, Daniel and Li, Changwei and Liu, Chunyu and Lloyd-Jone, Don and Loos, Ruth Jf and Mahaney, Michael C and Martin, Lisa W and Mathias, Rasika A and Minster, Ryan L and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Murabito, Joanne M and Naseri, Take and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Rao, Dabeeru C and Redline, Susan and Reiner, Alexander P and Rich, Stephen S and Ruepena, Muagututi{\textquoteright}a Sefuiva and Sheu, Wayne H-H and Smith, Jennifer A and Smith, Albert and Tiwari, Hemant K and Tsai, Michael Y and Viaud-Martinez, Karine A and Wang, Zhe and Yanek, Lisa R and Zhao, Wei and Rotter, Jerome I and Lin, Xihong and Natarajan, Pradeep and Peloso, Gina M} } @article {9543, title = {A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies.}, journal = {bioRxiv}, year = {2023}, month = {2023 Nov 02}, abstract = {

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of and an intergenic region on chromosome 1.

}, doi = {10.1101/2023.10.30.564764}, author = {Li, Xihao and Chen, Han and Selvaraj, Margaret Sunitha and Van Buren, Eric and Zhou, Hufeng and Wang, Yuxuan and Sun, Ryan and McCaw, Zachary R and Yu, Zhi and Arnett, Donna K and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Carson, April P and Carlson, Jenna C and Chami, Nathalie and Chen, Yii-Der Ida and Curran, Joanne E and de Vries, Paul S and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Gu, Charles and Heard-Costa, Nancy L and He, Jiang and Hou, Lifang and Hung, Yi-Jen and Irvin, Marguerite R and Kaplan, Robert C and Kardia, Sharon L R and Kelly, Tanika and Konigsberg, Iain and Kooperberg, Charles and Kral, Brian G and Li, Changwei and Loos, Ruth J F and Mahaney, Michael C and Martin, Lisa W and Mathias, Rasika A and Minster, Ryan L and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Reiner, Alexander P and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Tiwari, Hemant and Vasan, Ramachandran S and Wang, Zhe and Yanek, Lisa R and Yu, Bing and Rice, Kenneth M and Rotter, Jerome I and Peloso, Gina M and Natarajan, Pradeep and Li, Zilin and Liu, Zhonghua and Lin, Xihong} } @article {9450, title = {Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.}, journal = {medRxiv}, year = {2023}, month = {2023 Jul 28}, abstract = {

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD.

METHODS: From 16 studies of the Cohorts for Heart \& Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D.

RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2\%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance ( <5.0{\texttimes}10 ): rs147138607 (intergenic variant between and ) with a hazard ratio (HR) 1.23, 95\% confidence interval (CI) 1.15 - 1.32, =3.6{\texttimes}10 , rs11444867 (intergenic variant near ) with HR 1.89, 95\% CI 1.52 - 2.35, =9.9{\texttimes}10 , and rs335407 (intergenic variant between and ) HR 1.25, 95\% CI 1.16 - 1.35, =1.5{\texttimes}10 . Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with <0.05, and 5 were significant after Bonferroni correction ( <0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95\% CI 1.12 - 1.16) per 1 standard deviation increase ( =1.0{\texttimes}10 ).

CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

CLINICAL PERSPECTIVE: We conducted a large-scale multi-ancestry time-to-event GWAS to identify genetic variants associated with CVD among people with T2D. Three variants were significantly associated with incident CVD in people with T2D: rs147138607 (intergenic variant between and ), rs11444867 (intergenic variant near ), and rs335407 (intergenic variant between and ). A polygenic score composed of known CAD variants identified in the general population was significantly associated with the risk of CVD in people with T2D. There are genetic risk factors specific to T2D that could at least partially explain the excess risk of CVD in people with T2D.In addition, we show that people with T2D have enrichment of known CAD association signals which could also explain the excess risk of CVD.

}, doi = {10.1101/2023.07.25.23293180}, author = {Kwak, Soo Heon and Hernandez-Cancela, Ryan B and DiCorpo, Daniel A and Condon, David E and Merino, Jordi and Wu, Peitao and Brody, Jennifer A and Yao, Jie and Guo, Xiuqing and Ahmadizar, Fariba and Meyer, Mariah and Sincan, Murat and Mercader, Josep M and Lee, Sujin and Haessler, Jeffrey and Vy, Ha My T and Lin, Zhaotong and Armstrong, Nicole D and Gu, Shaopeng and Tsao, Noah L and Lange, Leslie A and Wang, Ningyuan and Wiggins, Kerri L and Trompet, Stella and Liu, Simin and Loos, Ruth J F and Judy, Renae and Schroeder, Philip H and Hasbani, Natalie R and Bos, Maxime M and Morrison, Alanna C and Jackson, Rebecca D and Reiner, Alexander P and Manson, JoAnn E and Chaudhary, Ninad S and Carmichael, Lynn K and Chen, Yii-Der Ida and Taylor, Kent D and Ghanbari, Mohsen and van Meurs, Joyce and Pitsillides, Achilleas N and Psaty, Bruce M and Noordam, Raymond and Do, Ron and Park, Kyong Soo and Jukema, J Wouter and Kavousi, Maryam and Correa, Adolfo and Rich, Stephen S and Damrauer, Scott M and Hajek, Catherine and Cho, Nam H and Irvin, Marguerite R and Pankow, James S and Nadkarni, Girish N and Sladek, Robert and Goodarzi, Mark O and Florez, Jose C and Chasman, Daniel I and Heckbert, Susan R and Kooperberg, Charles and Dupuis, Jos{\'e}e and Malhotra, Rajeev and de Vries, Paul S and Liu, Ching-Ti and Rotter, Jerome I and Meigs, James B} } @article {9537, title = {Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.}, journal = {Circ Genom Precis Med}, year = {2023}, month = {2023 Nov 28}, pages = {e004176}, abstract = {

BACKGROUND: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

METHODS: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test.

RESULTS: Using a Bonferroni-corrected significance threshold of <1.6{\texttimes}10, we identified 3 genes (, , and ) associated with CAC and 2 genes ( and ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both and also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.

CONCLUSIONS: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.123.004176}, author = {Hasbani, Natalie R and Westerman, Kenneth E and Heon Kwak, Soo and Chen, Han and Li, Xihao and DiCorpo, Daniel and Wessel, Jennifer and Bis, Joshua C and Sarnowski, Chloe and Wu, Peitao and Bielak, Lawrence F and Guo, Xiuqing and Heard-Costa, Nancy and Kinney, Gregory and Mahaney, Michael C and Montasser, May E and Palmer, Nicholette D and Raffield, Laura M and Terry, James G and Yanek, Lisa R and Bon, Jessica and Bowden, Donald W and Brody, Jennifer A and Duggirala, Ravindranath and Jacobs, David R and Kalyani, Rita R and Lange, Leslie A and Mitchell, Braxton D and Smith, Jennifer A and Taylor, Kent D and Carson, April and Curran, Joanne E and Fornage, Myriam and Freedman, Barry I and Gabriel, Stacey and Gibbs, Richard A and Gupta, Namrata and Kardia, Sharon L R and Kral, Brian G and Momin, Zeineen and Newman, Anne B and Post, Wendy S and Viaud-Martinez, Karine A and Young, Kendra A and Becker, Lewis C and Bertoni, Alain and Blangero, John and Carr, John J and Pratte, Katherine and Psaty, Bruce M and Rich, Stephen S and Wu, Joseph C and Malhotra, Rajeev and Peyser, Patricia A and Morrison, Alanna C and Vasan, Ramachandran S and Lin, Xihong and Rotter, Jerome I and Meigs, James B and Manning, Alisa K and de Vries, Paul S} } @article {9449, title = {Whole genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles.}, journal = {medRxiv}, year = {2023}, month = {2023 Jun 12}, abstract = {

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{\textquoteright}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.

}, doi = {10.1101/2023.06.07.23291095}, author = {Huffman, Jennifer E and Nicolas, Jayna and Hahn, Julie and Heath, Adam S and Raffield, Laura M and Yanek, Lisa R and Brody, Jennifer A and Thibord, Florian and Almasy, Laura and Bartz, Traci M and Bielak, Lawrence F and Bowler, Russell P and Carrasquilla, Germ{\'a}n D and Chasman, Daniel I and Chen, Ming-Huei and Emmert, David B and Ghanbari, Mohsen and Haessle, Jeffery and Hottenga, Jouke-Jan and Kleber, Marcus E and Le, Ngoc-Quynh and Lee, Jiwon and Lewis, Joshua P and Li-Gao, Ruifang and Luan, Jian{\textquoteright}an and Malmberg, Anni and Mangino, Massimo and Marioni, Riccardo E and Martinez-Perez, Angel and Pankratz, Nathan and Polasek, Ozren and Richmond, Anne and Rodriguez, Benjamin At and Rotter, Jerome I and Steri, Maristella and Suchon, Pierre and Trompet, Stella and Weiss, Stefan and Zare, Marjan and Auer, Paul and Cho, Michael H and Christofidou, Paraskevi and Davies, Gail and de Geus, Eco and Deleuze, Jean-Francois and Delgado, Graciela E and Ekunwe, Lynette and Faraday, Nauder and G{\"o}gele, Martin and Greinacher, Andreas and He, Gao and Howard, Tom and Joshi, Peter K and Kilpel{\"a}inen, Tuomas O and Lahti, Jari and Linneberg, Allan and Naitza, Silvia and Noordam, Raymond and Pa{\"u}ls-Verg{\'e}s, Ferran and Rich, Stephen S and Rosendaal, Frits R and Rudan, Igor and Ryan, Kathleen A and Souto, Juan Carlos and van Rooij, Frank Ja and Wang, Heming and Zhao, Wei and Becker, Lewis C and Beswick, Andrew and Brown, Michael R and Cade, Brian E and Campbell, Harry and Cho, Kelly and Crapo, James D and Curran, Joanne E and de Maat, Moniek Pm and Doyle, Margaret and Elliott, Paul and Floyd, James S and Fuchsberger, Christian and Grarup, Niels and Guo, Xiuqing and Harris, Sarah E and Hou, Lifang and Kolcic, Ivana and Kooperberg, Charles and Menni, Cristina and Nauck, Matthias and O{\textquoteright}Connell, Jeffrey R and Orr{\`u}, Valeria and Psaty, Bruce M and R{\"a}ikk{\"o}nen, Katri and Smith, Jennifer A and Soria, Jos{\'e} Manuel and Stott, David J and van Hylckama Vlieg, Astrid and Watkins, Hugh and Willemsen, Gonneke and Wilson, Peter and Ben-Shlomo, Yoav and Blangero, John and Boomsma, Dorret and Cox, Simon R and Dehghan, Abbas and Eriksson, Johan G and Fiorillo, Edoardo and Fornage, Myriam and Hansen, Torben and Hayward, Caroline and Ikram, M Arfan and Jukema, J Wouter and Kardia, Sharon Lr and Lange, Leslie A and M{\"a}rz, Winfried and Mathias, Rasika A and Mitchell, Braxton D and Mook-Kanamori, Dennis O and Morange, Pierre-Emmanuel and Pedersen, Oluf and Pramstaller, Peter P and Redline, Susan and Reiner, Alexander and Ridker, Paul M and Silverman, Edwin K and Spector, Tim D and V{\"o}lker, Uwe and Wareham, Nick and Wilson, James F and Yao, Jie and Tr{\'e}gou{\"e}t, David-Alexandre and Johnson, Andrew D and Wolberg, Alisa S and de Vries, Paul S and Sabater-Lleal, Maria and Morrison, Alanna C and Smith, Nicholas L} } @article {9581, title = {Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.}, journal = {Front Genet}, volume = {14}, year = {2023}, month = {2023}, pages = {1278215}, abstract = {

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{\textquoteright}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.

}, issn = {1664-8021}, doi = {10.3389/fgene.2023.1278215}, author = {Armstrong, Nicole D and Srinivasasainagendra, Vinodh and Ammous, Farah and Assimes, Themistocles L and Beitelshees, Amber L and Brody, Jennifer and Cade, Brian E and Ida Chen, Yii-Der and Chen, Han and de Vries, Paul S and Floyd, James S and Franceschini, Nora and Guo, Xiuqing and Hellwege, Jacklyn N and House, John S and Hwu, Chii-Min and Kardia, Sharon L R and Lange, Ethan M and Lange, Leslie A and McDonough, Caitrin W and Montasser, May E and O{\textquoteright}Connell, Jeffrey R and Shuey, Megan M and Sun, Xiao and Tanner, Rikki M and Wang, Zhe and Zhao, Wei and Carson, April P and Edwards, Todd L and Kelly, Tanika N and Kenny, Eimear E and Kooperberg, Charles and Loos, Ruth J F and Morrison, Alanna C and Motsinger-Reif, Alison and Psaty, Bruce M and Rao, Dabeeru C and Redline, Susan and Rich, Stephen S and Rotter, Jerome I and Smith, Jennifer A and Smith, Albert V and Irvin, Marguerite R and Arnett, Donna K} } @article {9707, title = {Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification.}, journal = {Nat Cardiovasc Res}, volume = {2}, year = {2023}, month = {2023 Dec}, pages = {1159-1172}, abstract = {

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC ( and ), with evidence of significant associations in replication analyses for both novel loci. Functional assays of and in human vascular smooth muscle cells (VSMCs) demonstrate that is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near with reduced CAC is likely explained by reduced expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease.

}, issn = {2731-0590}, doi = {10.1038/s44161-023-00375-y}, author = {de Vries, Paul S and Conomos, Matthew P and Singh, Kuldeep and Nicholson, Christopher J and Jain, Deepti and Hasbani, Natalie R and Jiang, Wanlin and Lee, Sujin and Lino Cardenas, Christian L and Lutz, Sharon M and Wong, Doris and Guo, Xiuqing and Yao, Jie and Young, Erica P and Tcheandjieu, Catherine and Hilliard, Austin T and Bis, Joshua C and Bielak, Lawrence F and Brown, Michael R and Musharoff, Shaila and Clarke, Shoa L and Terry, James G and Palmer, Nicholette D and Yanek, Lisa R and Xu, Huichun and Heard-Costa, Nancy and Wessel, Jennifer and Selvaraj, Margaret Sunitha and Li, Rebecca H and Sun, Xiao and Turner, Adam W and Stilp, Adrienne M and Khan, Alyna and Newman, Anne B and Rasheed, Asif and Freedman, Barry I and Kral, Brian G and McHugh, Caitlin P and Hodonsky, Chani and Saleheen, Danish and Herrington, David M and Jacobs, David R and Nickerson, Deborah A and Boerwinkle, Eric and Wang, Fei Fei and Heiss, Gerardo and Jun, Goo and Kinney, Greg L and Sigurslid, Haakon H and Doddapaneni, Harshavardhan and Hall, Ira M and Bensenor, Isabela M and Broome, Jai and Crapo, James D and Wilson, James G and Smith, Jennifer A and Blangero, John and Vargas, Jose D and Mosquera, Jose Verdezoto and Smith, Joshua D and Viaud-Martinez, Karine A and Ryan, Kathleen A and Young, Kendra A and Taylor, Kent D and Lange, Leslie A and Emery, Leslie S and Bittencourt, Marcio S and Budoff, Matthew J and Montasser, May E and Yu, Miao and Mahaney, Michael C and Mahamdeh, Mohammed S and Fornage, Myriam and Franceschini, Nora and Lotufo, Paulo A and Natarajan, Pradeep and Wong, Quenna and Mathias, Rasika A and Gibbs, Richard A and Do, Ron and Mehran, Roxana and Tracy, Russell P and Kim, Ryan W and Nelson, Sarah C and Damrauer, Scott M and Kardia, Sharon L R and Rich, Stephen S and Fuster, Valentin and Napolioni, Valerio and Zhao, Wei and Tian, Wenjie and Yin, Xianyong and Min, Yuan-I and Manning, Alisa K and Peloso, Gina and Kelly, Tanika N and O{\textquoteright}Donnell, Christopher J and Morrison, Alanna C and Curran, Joanne E and Zapol, Warren M and Bowden, Donald W and Becker, Lewis C and Correa, Adolfo and Mitchell, Braxton D and Psaty, Bruce M and Carr, John Jeffrey and Pereira, Alexandre C and Assimes, Themistocles L and Stitziel, Nathan O and Hokanson, John E and Laurie, Cecelia A and Rotter, Jerome I and Vasan, Ramachandran S and Post, Wendy S and Peyser, Patricia A and Miller, Clint L and Malhotra, Rajeev} } @article {9851, title = {The expected polygenic risk score (ePRS) framework: an equitable metric for quantifying polygenetic risk via modeling of ancestral makeup.}, journal = {medRxiv}, year = {2024}, month = {2024 Dec 20}, abstract = {

Polygenic risk scores (PRSs) depend on genetic ancestry due to differences in allele frequencies between ancestral populations. This leads to implementation challenges in diverse populations. We propose a framework to calibrate PRS based on ancestral makeup. We define a metric called "expected PRS" (ePRS), the expected value of a PRS based on one{\textquoteright}s global or local admixture patterns. We further define the "residual PRS" (rPRS), measuring the deviation of the PRS from the ePRS. Simulation studies confirm that it suffices to adjust for ePRS to obtain nearly unbiased estimates of the PRS-outcome association without further adjusting for PCs. Using the TOPMed dataset, the estimated effect size of the rPRS adjusting for the ePRS is similar to the estimated effect of the PRS adjusting for genetic PCs. Similarly, we applied the ePRS framework to six cardiovascular-related traits in the All of Us dataset, and the results are consistent with those from the TOPMed analysis. The ePRS framework can protect from population stratification in association analysis and provide an equitable strategy to quantify genetic risk across diverse populations.

}, doi = {10.1101/2024.03.05.24303738}, author = {Huang, Yu-Jyun and Kurniansyah, Nuzulul and Goodman, Matthew O and Spitzer, Brian W and Wang, Jiongming and Stilp, Adrienne and Laurie, Cecelia and de Vries, Paul S and Chen, Han and Min, Yuan-I and Sims, Mario and Peloso, Gina M and Guo, Xiuqing and Bis, Joshua C and Brody, Jennifer A and Raffield, Laura M and Smith, Jennifer A and Zhao, Wei and Rotter, Jerome I and Rich, Stephen S and Redline, Susan and Fornage, Myriam and Kaplan, Robert and Franceschini, Nora and Levy, Daniel and Morrison, Alanna C and Boerwinkle, Eric and Smith, Nicholas L and Kooperberg, Charles and Psaty, Bruce M and Z{\"o}llner, Sebastian and Sofer, Tamar} } @article {9642, title = {A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.}, journal = {medRxiv}, year = {2024}, month = {2024 Mar 08}, abstract = {

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management.

}, doi = {10.1101/2024.03.07.24303870}, author = {Nagarajan, Pavithra and Winkler, Thomas W and Bentley, Amy R and Miller, Clint L and Kraja, Aldi T and Schwander, Karen and Lee, Songmi and Wang, Wenyi and Brown, Michael R and Morrison, John L and Giri, Ayush and O{\textquoteright}Connell, Jeffrey R and Bartz, Traci M and de Las Fuentes, Lisa and Gudmundsdottir, Valborg and Guo, Xiuqing and Harris, Sarah E and Huang, Zhijie and Kals, Mart and Kho, Minjung and Lefevre, Christophe and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Mangino, Massimo and Milaneschi, Yuri and Palmer, Nicholette D and Rao, Varun and Rauramaa, Rainer and Shen, Botong and Stadler, Stefan and Sun, Quan and Tang, Jingxian and Th{\'e}riault, S{\'e}bastien and van der Graaf, Adriaan and van der Most, Peter J and Wang, Yujie and Weiss, Stefan and Westerman, Kenneth E and Yang, Qian and Yasuharu, Tabara and Zhao, Wei and Zhu, Wanying and Altschul, Drew and Ansari, Md Abu Yusuf and Anugu, Pramod and Argoty-Pantoja, Anna D and Arzt, Michael and Aschard, Hugues and Attia, John R and Bazzanno, Lydia and Breyer, Max A and Brody, Jennifer A and Cade, Brian E and Chen, Hung-Hsin and Ida Chen, Yii-Der and Chen, Zekai and de Vries, Paul S and Dimitrov, Latchezar M and Do, Anh and Du, Jiawen and Dupont, Charles T and Edwards, Todd L and Evans, Michele K and Faquih, Tariq and Felix, Stephan B and Fisher-Hoch, Susan P and Floyd, James S and Graff, Mariaelisa and Gu, Charles and Gu, Dongfeng and Hairston, Kristen G and Hanley, Anthony J and Heid, Iris M and Heikkinen, Sami and Highland, Heather M and Hood, Michelle M and K{\"a}h{\"o}nen, Mika and Karvonen-Gutierrez, Carrie A and Kawaguchi, Takahisa and Kazuya, Setoh and Kelly, Tanika N and Komulainen, Pirjo and Levy, Daniel and Lin, Henry J and Liu, Peter Y and Marques-Vidal, Pedro and McCormick, Joseph B and Mei, Hao and Meigs, James B and Menni, Cristina and Nam, Kisung and Nolte, Ilja M and Pacheco, Natasha L and Petty, Lauren E and Polikowsky, Hannah G and Province, Michael A and Psaty, Bruce M and Raffield, Laura M and Raitakari, Olli T and Rich, Stephen S and Riha, Renata L and Risch, Lorenz and Risch, Martin and Ruiz-Narvaez, Edward A and Scott, Rodney J and Sitlani, Colleen M and Smith, Jennifer A and Sofer, Tamar and Teder-Laving, Maris and V{\"o}lker, Uwe and Vollenweider, Peter and Wang, Guanchao and van Dijk, Ko Willems and Wilson, Otis D and Xia, Rui and Yao, Jie and Young, Kristin L and Zhang, Ruiyuan and Zhu, Xiaofeng and Below, Jennifer E and B{\"o}ger, Carsten A and Conen, David and Cox, Simon R and D{\"o}rr, Marcus and Feitosa, Mary F and Fox, Ervin R and Franceschini, Nora and Gharib, Sina A and Gudnason, Vilmundur and Harlow, Sioban D and He, Jiang and Holliday, Elizabeth G and Kutalik, Zolt{\'a}n and Lakka, Timo A and Lawlor, Deborah A and Lee, Seunggeun and Lehtim{\"a}ki, Terho and Li, Changwei and Liu, Ching-Ti and M{\"a}gi, Reedik and Matsuda, Fumihiko and Morrison, Alanna C and Penninx, Brenda Wjh and Peyser, Patricia A and Rotter, Jerome I and Snieder, Harold and Spector, Tim D and Wagenknecht, Lynne E and Wareham, Nicholas J and Zonderman, Alan B and North, Kari E and Fornage, Myriam and Hung, Adriana M and Manning, Alisa K and Gauderman, James and Chen, Han and Munroe, Patricia B and Rao, Dabeeru C and van Heemst, Diana and Redline, Susan and Noordam, Raymond and Wang, Heming} } @article {9787, title = {Rare variant contribution to the heritability of coronary artery disease.}, journal = {Nat Commun}, volume = {15}, year = {2024}, month = {2024 Oct 09}, pages = {8741}, abstract = {

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3\% assuming a prevalence of 8.2\%. Ultra-rare (minor allele frequency <= 0.1\%) variants with low linkage disequilibrium (LD) score contribute ~50\% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

}, keywords = {Case-Control Studies, Coronary Artery Disease, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, White People, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-024-52939-6}, author = {Rocheleau, Ghislain and Clarke, Shoa L and Auguste, Ga{\"e}lle and Hasbani, Natalie R and Morrison, Alanna C and Heath, Adam S and Bielak, Lawrence F and Iyer, Kruthika R and Young, Erica P and Stitziel, Nathan O and Jun, Goo and Laurie, Cecelia and Broome, Jai G and Khan, Alyna T and Arnett, Donna K and Becker, Lewis C and Bis, Joshua C and Boerwinkle, Eric and Bowden, Donald W and Carson, April P and Ellinor, Patrick T and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Heard-Costa, Nancy L and Hou, Lifang and Chen, Yii-Der Ida and Kenny, Eimear E and Kooperberg, Charles and Kral, Brian G and Loos, Ruth J F and Lutz, Sharon M and Manson, JoAnn E and Martin, Lisa W and Mitchell, Braxton D and Nassir, Rami and Palmer, Nicholette D and Post, Wendy S and Preuss, Michael H and Psaty, Bruce M and Raffield, Laura M and Regan, Elizabeth A and Rich, Stephen S and Smith, Jennifer A and Taylor, Kent D and Yanek, Lisa R and Young, Kendra A and Hilliard, Austin T and Tcheandjieu, Catherine and Peyser, Patricia A and Vasan, Ramachandran S and Rotter, Jerome I and Miller, Clint L and Assimes, Themistocles L and de Vries, Paul S and Do, Ron} } @article {9667, title = {Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.}, journal = {Diabetes Care}, year = {2024}, month = {2024 Apr 23}, abstract = {

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D).

RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD.

RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2\%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 {\texttimes} 10-9), rs11444867 (near HS3ST1, HR 1.89, P = 9.9 {\texttimes} 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 {\texttimes} 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 {\texttimes} 10-16).

CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

}, issn = {1935-5548}, doi = {10.2337/dc23-2274}, author = {Kwak, Soo Heon and Hernandez-Cancela, Ryan B and DiCorpo, Daniel A and Condon, David E and Merino, Jordi and Wu, Peitao and Brody, Jennifer A and Yao, Jie and Guo, Xiuqing and Ahmadizar, Fariba and Meyer, Mariah and Sincan, Murat and Mercader, Josep M and Lee, Sujin and Haessler, Jeffrey and Vy, Ha My T and Lin, Zhaotong and Armstrong, Nicole D and Gu, Shaopeng and Tsao, Noah L and Lange, Leslie A and Wang, Ningyuan and Wiggins, Kerri L and Trompet, Stella and Liu, Simin and Loos, Ruth J F and Judy, Renae and Schroeder, Philip H and Hasbani, Natalie R and Bos, Maxime M and Morrison, Alanna C and Jackson, Rebecca D and Reiner, Alexander P and Manson, JoAnn E and Chaudhary, Ninad S and Carmichael, Lynn K and Chen, Yii-Der Ida and Taylor, Kent D and Ghanbari, Mohsen and van Meurs, Joyce and Pitsillides, Achilleas N and Psaty, Bruce M and Noordam, Raymond and Do, Ron and Park, Kyong Soo and Jukema, J Wouter and Kavousi, Maryam and Correa, Adolfo and Rich, Stephen S and Damrauer, Scott M and Hajek, Catherine and Cho, Nam H and Irvin, Marguerite R and Pankow, James S and Nadkarni, Girish N and Sladek, Robert and Goodarzi, Mark O and Florez, Jose C and Chasman, Daniel I and Heckbert, Susan R and Kooperberg, Charles and Dupuis, Jos{\'e}e and Malhotra, Rajeev and de Vries, Paul S and Liu, Ching-Ti and Rotter, Jerome I and Meigs, James B} } @article {9866, title = {Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.}, journal = {Am J Hum Genet}, volume = {112}, year = {2025}, month = {2025 Feb 06}, pages = {276-290}, abstract = {

Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones.

}, keywords = {Alleles, Chromosome Deletion, Chromosomes, Human, Y, Genomics, Haplotypes, Humans, Male, Mosaicism, Phenotype, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2024.12.014}, author = {Jakubek, Yasminka A and Ma, Xiaolong and Stilp, Adrienne M and Yu, Fulong and Bacon, Jason and Wong, Justin W and Aguet, Francois and Ardlie, Kristin and Arnett, Donna K and Barnes, Kathleen and Bis, Joshua C and Blackwell, Tom and Becker, Lewis C and Boerwinkle, Eric and Bowler, Russell P and Budoff, Matthew J and Carson, April P and Chen, Jiawen and Cho, Michael H and Coresh, Josef and Cox, Nancy J and de Vries, Paul S and DeMeo, Dawn L and Fardo, David W and Fornage, Myriam and Guo, Xiuqing and Hall, Michael E and Heard-Costa, Nancy and Hidalgo, Bertha and Irvin, Marguerite Ryan and Johnson, Andrew D and Jorgenson, Eric and Kenny, Eimear E and Kessler, Michael D and Levy, Daniel and Li, Yun and Lima, Jo{\~a}o A C and Liu, Yongmei and Locke, Adam E and Loos, Ruth J F and Machiela, Mitchell J and Mathias, Rasika A and Mitchell, Braxton D and Murabito, Joanne M and Mychaleckyj, Josyf C and North, Kari E and Orchard, Peter and Parker, Stephen C J and Pershad, Yash and Peyser, Patricia A and Pratte, Katherine A and Psaty, Bruce M and Raffield, Laura M and Redline, Susan and Rich, Stephen S and Rotter, Jerome I and Shah, Sanjiv J and Smith, Jennifer A and Smith, Aaron P and Smith, Albert and Taub, Margaret A and Tiwari, Hemant K and Tracy, Russell and Tuftin, Bjoernar and Bick, Alexander G and Sankaran, Vijay G and Reiner, Alexander P and Scheet, Paul and Auer, Paul L} } @article {9912, title = {A Large-Scale Genome-wide Association Study of Blood Pressure Accounting for Gene-Depressive Symptomatology Interactions in 564,680 Individuals from Diverse Populations.}, journal = {Res Sq}, year = {2025}, month = {2025 Feb 17}, abstract = {

BACKGROUND: Gene-environment interactions may enhance our understanding of hypertension. Our previous study highlighted the importance of considering psychosocial factors in gene discovery for blood pressure (BP) but was limited in statistical power and population diversity. To address these challenges, we conducted a multi-population genome-wide association study (GWAS) of BP accounting for gene-depressive symptomatology (DEPR) interactions in a larger and more diverse sample.

RESULTS: Our study included 564,680 adults aged 18 years or older from 67 cohorts and 4 population backgrounds (African (5\%), Asian (7\%), European (85\%), and Hispanic (3\%)). We discovered seven novel gene-DEPR interaction loci for BP traits. These loci mapped to genes implicated in neurogenesis (), lipid metabolism (), neuronal apoptosis (), and synaptic activity (). We also identified evidence for gene-DEPR interaction at nine known BP loci, further suggesting links between mood disturbance and BP regulation. Of the 16 identified loci, 11 loci were derived from African, Asian, or Hispanic populations. Post-GWAS analyses prioritized 36 genes, including genes involved in synaptic functions () and neuronal signaling (). Integrative druggability analyses identified 11 druggable candidate gene targets, including genes implicated in pathways linked to mood disorders as well as gene products targeted by known antihypertensive drugs.

CONCLUSIONS: Our findings emphasize the importance of considering gene-DEPR interactions on BP, particularly in non-European populations. Our prioritized genes and druggable targets highlight biological pathways connecting mood disorders and hypertension and suggest opportunities for BP drug repurposing and risk factor prevention, especially in individuals with DEPR.

}, issn = {2693-5015}, doi = {10.21203/rs.3.rs-6025759/v1}, author = {Lee, Songmi and Miller, Clint L and Bentley, Amy R and Brown, Michael R and Nagarajan, Pavithra and Noordam, Raymond and Morrison, John and Schwander, Karen and Westerman, Kenneth and Kho, Minjung and Kraja, Aldi T and de Vries, Paul S and Ammous, Farah and Aschard, Hughes and Bartz, Traci M and Do, Anh and Dupont, Charles T and Feitosa, Mary F and Gudmundsdottir, Valborg and Guo, Xiuqing and Harris, Sarah E and Hikino, Keiko and Huang, Zhijie and Lefevre, Christophe and Lyytik{\"a}inen, Leo-Pekka and Milaneschi, Yuri and Nardone, Giuseppe Giovanni and Santin, Aurora and Schmidt, Helena and Shen, Botong and Sofer, Tamar and Sun, Quan and Tan, Ye An and Tang, Jingxian and Th{\'e}riault, S{\'e}bastien and van der Most, Peter J and Ware, Erin B and Weiss, Stefan and Ya Xing, Wang and Yu, Chenglong and Zhao, Wei and Ansari, Md Abu Yusuf and Anugu, Pramod and Attia, John R and Bazzano, Lydia A and Bis, Joshua C and Breyer, Max and Cade, Brian and Chen, Guanjie and Collins, Stacey and Corley, Janie and Davies, Gail and D{\"o}rr, Marcus and Du, Jiawen and Edwards, Todd L and Faquih, Tariq and Faul, Jessica D and Fohner, Alison E and Fretts, Amanda M and Gangireddy, Srushti and Gepner, Adam and Graff, Mariaelisa and Hofer, Edith and Homuth, Georg and Hood, Michelle M and Jie, Xu and K{\"a}h{\"o}nen, Mika and Kardia, Sharon Lr and Karvonen-Gutierrez, Carrie A and Launer, Lenore J and Levy, Daniel and Maheshwari, Maitreiyi and Martin, Lisa W and Matsuda, Koichi and McNeil, John J and Nolte, Ilja M and Okochi, Tomo and Raffield, Laura M and Raitakari, Olli T and Risch, Lorenz and Risch, Martin and Roux, Ana Diez and Ruiz-Narvaez, Edward A and Russ, Tom C and Saito, Takeo and Schreiner, Pamela J and Scott, Rodney J and Shikany, James and Smith, Jennifer A and Snieder, Harold and Spedicati, Beatrice and Tai, E Shyong and Taylor, Adele M and Taylor, Kent D and Tesolin, Paola and van Dam, Rob M and Wang, Rujia and Wenbin, Wei and Xie, Tian and Yao, Jie and Young, Kristin L and Zhang, Ruiyuan and Zonderman, Alan B and Concas, Maria Pina and Conen, David and Cox, Simon R and Evans, Michele K and Fox, Ervin R and de Las Fuentes, Lisa and Giri, Ayush and Girotto, Giorgia and Grabe, Hans J and Gu, Charles and Gudnason, Vilmundur and Harlow, Sioban D and Holliday, Elizabeth and Jost, Jonas B and Lacaze, Paul and Lee, Seunggeun and Lehtim{\"a}ki, Terho and Li, Changwei and Liu, Ching-Ti and Morrison, Alanna C and North, Kari E and Penninx, Brenda Wjh and Peyser, Patricia A and Province, Michael M and Psaty, Bruce M and Redline, Susan and Rosendaal, Frits R and Rotimi, Charles N and Rotter, Jerome I and Schmidt, Reinhold and Sim, Xueling and Terao, Chikashi and Weir, David R and Zhu, Xiaofeng and Franceschini, Nora and O{\textquoteright}Connell, Jeffrey R and Jaquish, Cashell E and Wang, Heming and Manning, Alisa and Munroe, Patricia B and Rao, Dabeeru C and Chen, Han and Gauderman, W James and Bierut, Laura and Winkler, Thomas W and Fornage, Myriam} } @article {9900, title = {A large-scale genome-wide study of gene-sleep duration interactions for blood pressure in 811,405 individuals from diverse populations.}, journal = {Mol Psychiatry}, year = {2025}, month = {2025 Apr 04}, abstract = {

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discovered 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes{\textquoteright} functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.

}, issn = {1476-5578}, doi = {10.1038/s41380-025-02954-w}, author = {Nagarajan, Pavithra and Winkler, Thomas W and Bentley, Amy R and Miller, Clint L and Kraja, Aldi T and Schwander, Karen and Lee, Songmi and Wang, Wenyi and Brown, Michael R and Morrison, John L and Giri, Ayush and O{\textquoteright}Connell, Jeffrey R and Bartz, Traci M and de Las Fuentes, Lisa and Gudmundsdottir, Valborg and Guo, Xiuqing and Harris, Sarah E and Huang, Zhijie and Kals, Mart and Kho, Minjung and Lefevre, Christophe and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Mangino, Massimo and Milaneschi, Yuri and Palmer, Nicholette D and Rao, Varun and Rauramaa, Rainer and Shen, Botong and Stadler, Stefan and Sun, Quan and Tang, Jingxian and Th{\'e}riault, S{\'e}bastien and van der Graaf, Adriaan and van der Most, Peter J and Wang, Yujie and Weiss, Stefan and Westerman, Kenneth E and Yang, Qian and Yasuharu, Tabara and Zhao, Wei and Zhu, Wanying and Altschul, Drew and Ansari, Md Abu Yusuf and Anugu, Pramod and Argoty-Pantoja, Anna D and Arzt, Michael and Aschard, Hugues and Attia, John R and Bazzanno, Lydia and Breyer, Max A and Brody, Jennifer A and Cade, Brian E and Chen, Hung-Hsin and Chen, Yii-Der Ida and Chen, Zekai and de Vries, Paul S and Dimitrov, Latchezar M and Do, Anh and Du, Jiawen and Dupont, Charles T and Edwards, Todd L and Evans, Michele K and Faquih, Tariq and Felix, Stephan B and Fisher-Hoch, Susan P and Floyd, James S and Graff, Mariaelisa and Gu, Charles and Gu, Dongfeng and Hairston, Kristen G and Hanley, Anthony J and Heid, Iris M and Heikkinen, Sami and Highland, Heather M and Hood, Michelle M and K{\"a}h{\"o}nen, Mika and Karvonen-Gutierrez, Carrie A and Kawaguchi, Takahisa and Kazuya, Setoh and Kelly, Tanika N and Komulainen, Pirjo and Levy, Daniel and Lin, Henry J and Liu, Peter Y and Marques-Vidal, Pedro and McCormick, Joseph B and Mei, Hao and Meigs, James B and Menni, Cristina and Nam, Kisung and Nolte, Ilja M and Pacheco, Natasha L and Petty, Lauren E and Polikowsky, Hannah G and Province, Michael A and Psaty, Bruce M and Raffield, Laura M and Raitakari, Olli T and Rich, Stephen S and Riha, Renata L and Risch, Lorenz and Risch, Martin and Ruiz-Narvaez, Edward A and Scott, Rodney J and Sitlani, Colleen M and Smith, Jennifer A and Sofer, Tamar and Teder-Laving, Maris and V{\"o}lker, Uwe and Vollenweider, Peter and Wang, Guanchao and Willems van Dijk, Ko and Wilson, Otis D and Xia, Rui and Yao, Jie and Young, Kristin L and Zhang, Ruiyuan and Zhu, Xiaofeng and Below, Jennifer E and B{\"o}ger, Carsten A and Conen, David and Cox, Simon R and D{\"o}rr, Marcus and Feitosa, Mary F and Fox, Ervin R and Franceschini, Nora and Gharib, Sina A and Gudnason, Vilmundur and Harlow, Sioban D and He, Jiang and Holliday, Elizabeth G and Kutalik, Zolt{\'a}n and Lakka, Timo A and Lawlor, Deborah A and Lee, Seunggeun and Lehtim{\"a}ki, Terho and Li, Changwei and Liu, Ching-Ti and M{\"a}gi, Reedik and Matsuda, Fumihiko and Morrison, Alanna C and Penninx, Brenda Wjh and Peyser, Patricia A and Rotter, Jerome I and Snieder, Harold and Spector, Tim D and Wagenknecht, Lynne E and Wareham, Nicholas J and Zonderman, Alan B and North, Kari E and Fornage, Myriam and Hung, Adriana M and Manning, Alisa K and Gauderman, James and Chen, Han and Munroe, Patricia B and Rao, Dabeeru C and van Heemst, Diana and Redline, Susan and Noordam, Raymond and Wang, Heming} } @article {9898, title = {Rare damaging CCR2 variants are associated with lower lifetime cardiovascular risk.}, journal = {Genome Med}, volume = {17}, year = {2025}, month = {2025 Mar 21}, pages = {27}, abstract = {

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested in migration and cAMP assays. Validated damaging variants were tested for association with cardiovascular endpoints, atherosclerosis burden, and vascular risk factors. Significant associations were replicated in six independent datasets (n = 1,062,595).

RESULTS: Carriers of 45 predicted damaging or loss-of-function CCR2 variants (n = 787 individuals) were at lower risk of myocardial infarction and coronary artery disease. One of these variants (M249K, n = 585, 0.15\% of European ancestry individuals) was associated with lower monocyte count and with both decreased downstream signaling and chemoattraction in response to CCL2. While M249K showed no association with conventional vascular risk factors, it was consistently associated with a lower risk of myocardial infarction (odds ratio [OR]: 0.66, 95\% confidence interval [CI]: 0.54-0.81, p = 6.1 {\texttimes} 10) and coronary artery disease (OR: 0.74, 95\%CI: 0.63-0.87, p = 2.9 {\texttimes} 10) in the UK Biobank and in six replication cohorts. In a phenome-wide association study, there was no evidence of a higher risk of infections among M249K carriers.

CONCLUSIONS: Carriers of an experimentally confirmed damaging CCR2 variant are at a lower lifetime risk of myocardial infarction and coronary artery disease without carrying a higher risk of infections. Our findings provide genetic support for the translational potential of CCR2-targeting as an atheroprotective approach.

}, keywords = {Aged, Cardiovascular Diseases, Chemokine CCL2, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Monocytes, Receptors, CCR2}, issn = {1756-994X}, doi = {10.1186/s13073-025-01456-2}, author = {Georgakis, Marios K and Malik, Rainer and Bounkari, Omar El and Hasbani, Natalie R and Li, Jiang and Huffman, Jennifer E and Shakt, Gabrielle and Tack, Reinier W P and Kimball, Tamara N and Asare, Yaw and Morrison, Alanna C and Tsao, Noah L and Judy, Renae and Mitchell, Braxton D and Xu, Huichun and Montasser, May E and Do, Ron and Kenny, Eimear E and Loos, Ruth J F and Terry, James G and Carr, John Jeffrey and Bis, Joshua C and Psaty, Bruce M and Longstreth, W T and Young, Kendra A and Lutz, Sharon M and Cho, Michael H and Broome, Jai and Khan, Alyna T and Wang, Fei Fei and Heard-Costa, Nancy and Seshadri, Sudha and Vasan, Ramachandran S and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Yanek, Lisa R and Kral, Brian G and Becker, Lewis C and Peyser, Patricia A and Bielak, Lawrence F and Ammous, Farah and Carson, April P and Hall, Michael E and Raffield, Laura M and Rich, Stephen S and Post, Wendy S and Tracy, Russel P and Taylor, Kent D and Guo, Xiuqing and Mahaney, Michael C and Curran, Joanne E and Blangero, John and Clarke, Shoa L and Haessler, Jeffrey W and Hu, Yao and Assimes, Themistocles L and Kooperberg, Charles and Bernhagen, J{\"u}rgen and Anderson, Christopher D and Damrauer, Scott M and Zand, Ramin and Rotter, Jerome I and de Vries, Paul S and Dichgans, Martin} } @article {9899, title = {A statistical framework for multi-trait rare variant analysis in large-scale whole-genome sequencing studies.}, journal = {Nat Comput Sci}, volume = {5}, year = {2025}, month = {2025 Feb}, pages = {125-143}, abstract = {

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally scalable analytical pipeline for functionally informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits in 61,838 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered and replicated new associations with lipid traits missed by single-trait analysis.

}, keywords = {Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Lipids, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Whole Genome Sequencing}, issn = {2662-8457}, doi = {10.1038/s43588-024-00764-8}, author = {Li, Xihao and Chen, Han and Selvaraj, Margaret Sunitha and Van Buren, Eric and Zhou, Hufeng and Wang, Yuxuan and Sun, Ryan and McCaw, Zachary R and Yu, Zhi and Jiang, Min-Zhi and DiCorpo, Daniel and Gaynor, Sheila M and Dey, Rounak and Arnett, Donna K and Benjamin, Emelia J and Bis, Joshua C and Blangero, John and Boerwinkle, Eric and Bowden, Donald W and Brody, Jennifer A and Cade, Brian E and Carson, April P and Carlson, Jenna C and Chami, Nathalie and Chen, Yii-Der Ida and Curran, Joanne E and de Vries, Paul S and Fornage, Myriam and Franceschini, Nora and Freedman, Barry I and Gu, Charles and Heard-Costa, Nancy L and He, Jiang and Hou, Lifang and Hung, Yi-Jen and Irvin, Marguerite R and Kaplan, Robert C and Kardia, Sharon L R and Kelly, Tanika N and Konigsberg, Iain and Kooperberg, Charles and Kral, Brian G and Li, Changwei and Li, Yun and Lin, Honghuang and Liu, Ching-Ti and Loos, Ruth J F and Mahaney, Michael C and Martin, Lisa W and Mathias, Rasika A and Mitchell, Braxton D and Montasser, May E and Morrison, Alanna C and Naseri, Take and North, Kari E and Palmer, Nicholette D and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Reiner, Alexander P and Rich, Stephen S and Sitlani, Colleen M and Smith, Jennifer A and Taylor, Kent D and Tiwari, Hemant K and Vasan, Ramachandran S and Viali, Satupa{\textquoteright}itea and Wang, Zhe and Wessel, Jennifer and Yanek, Lisa R and Yu, Bing and Dupuis, Jos{\'e}e and Meigs, James B and Auer, Paul L and Raffield, Laura M and Manning, Alisa K and Rice, Kenneth M and Rotter, Jerome I and Peloso, Gina M and Natarajan, Pradeep and Li, Zilin and Liu, Zhonghua and Lin, Xihong} }