@article {8621, title = {Inherited causes of clonal haematopoiesis in 97,691 whole genomes.}, journal = {Nature}, volume = {586}, year = {2020}, month = {2020 10}, pages = {763-768}, abstract = {

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

}, issn = {1476-4687}, doi = {10.1038/s41586-020-2819-2}, author = {Bick, Alexander G and Weinstock, Joshua S and Nandakumar, Satish K and Fulco, Charles P and Bao, Erik L and Zekavat, Seyedeh M and Szeto, Mindy D and Liao, Xiaotian and Leventhal, Matthew J and Nasser, Joseph and Chang, Kyle and Laurie, Cecelia and Burugula, Bala Bharathi and Gibson, Christopher J and Lin, Amy E and Taub, Margaret A and Aguet, Francois and Ardlie, Kristin and Mitchell, Braxton D and Barnes, Kathleen C and Moscati, Arden and Fornage, Myriam and Redline, Susan and Psaty, Bruce M and Silverman, Edwin K and Weiss, Scott T and Palmer, Nicholette D and Vasan, Ramachandran S and Burchard, Esteban G and Kardia, Sharon L R and He, Jiang and Kaplan, Robert C and Smith, Nicholas L and Arnett, Donna K and Schwartz, David A and Correa, Adolfo and de Andrade, Mariza and Guo, Xiuqing and Konkle, Barbara A and Custer, Brian and Peralta, Juan M and Gui, Hongsheng and Meyers, Deborah A and McGarvey, Stephen T and Chen, Ida Yii-Der and Shoemaker, M Benjamin and Peyser, Patricia A and Broome, Jai G and Gogarten, Stephanie M and Wang, Fei Fei and Wong, Quenna and Montasser, May E and Daya, Michelle and Kenny, Eimear E and North, Kari E and Launer, Lenore J and Cade, Brian E and Bis, Joshua C and Cho, Michael H and Lasky-Su, Jessica and Bowden, Donald W and Cupples, L Adrienne and Mak, Angel C Y and Becker, Lewis C and Smith, Jennifer A and Kelly, Tanika N and Aslibekyan, Stella and Heckbert, Susan R and Tiwari, Hemant K and Yang, Ivana V and Heit, John A and Lubitz, Steven A and Johnsen, Jill M and Curran, Joanne E and Wenzel, Sally E and Weeks, Daniel E and Rao, Dabeeru C and Darbar, Dawood and Moon, Jee-Young and Tracy, Russell P and Buth, Erin J and Rafaels, Nicholas and Loos, Ruth J F and Durda, Peter and Liu, Yongmei and Hou, Lifang and Lee, Jiwon and Kachroo, Priyadarshini and Freedman, Barry I and Levy, Daniel and Bielak, Lawrence F and Hixson, James E and Floyd, James S and Whitsel, Eric A and Ellinor, Patrick T and Irvin, Marguerite R and Fingerlin, Tasha E and Raffield, Laura M and Armasu, Sebastian M and Wheeler, Marsha M and Sabino, Ester C and Blangero, John and Williams, L Keoki and Levy, Bruce D and Sheu, Wayne Huey-Herng and Roden, Dan M and Boerwinkle, Eric and Manson, JoAnn E and Mathias, Rasika A and Desai, Pinkal and Taylor, Kent D and Johnson, Andrew D and Auer, Paul L and Kooperberg, Charles and Laurie, Cathy C and Blackwell, Thomas W and Smith, Albert V and Zhao, Hongyu and Lange, Ethan and Lange, Leslie and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Scheet, Paul and Kitzman, Jacob O and Lander, Eric S and Engreitz, Jesse M and Ebert, Benjamin L and Reiner, Alexander P and Jaiswal, Siddhartha and Abecasis, Goncalo and Sankaran, Vijay G and Kathiresan, Sekar and Natarajan, Pradeep} } @article {8490, title = {The Polygenic and Monogenic Basis of Blood Traits and Diseases.}, journal = {Cell}, volume = {182}, year = {2020}, month = {2020 Sep 03}, pages = {1214-1231.e11}, abstract = {

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

}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.08.008}, author = {Vuckovic, Dragana and Bao, Erik L and Akbari, Parsa and Lareau, Caleb A and Mousas, Abdou and Jiang, Tao and Chen, Ming-Huei and Raffield, Laura M and Tardaguila, Manuel and Huffman, Jennifer E and Ritchie, Scott C and Megy, Karyn and Ponstingl, Hannes and Penkett, Christopher J and Albers, Patrick K and Wigdor, Emilie M and Sakaue, Saori and Moscati, Arden and Manansala, Regina and Lo, Ken Sin and Qian, Huijun and Akiyama, Masato and Bartz, Traci M and Ben-Shlomo, Yoav and Beswick, Andrew and Bork-Jensen, Jette and Bottinger, Erwin P and Brody, Jennifer A and van Rooij, Frank J A and Chitrala, Kumaraswamy N and Wilson, Peter W F and Choquet, Helene and Danesh, John and Di Angelantonio, Emanuele and Dimou, Niki and Ding, Jingzhong and Elliott, Paul and Esko, T{\~o}nu and Evans, Michele K and Felix, Stephan B and Floyd, James S and Broer, Linda and Grarup, Niels and Guo, Michael H and Guo, Qi and Greinacher, Andreas and Haessler, Jeff and Hansen, Torben and Howson, Joanna M M and Huang, Wei and Jorgenson, Eric and Kacprowski, Tim and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanai, Masahiro and Karthikeyan, Savita and Koskeridis, Fotios and Lange, Leslie A and Lehtim{\"a}ki, Terho and Linneberg, Allan and Liu, Yongmei and Lyytik{\"a}inen, Leo-Pekka and Manichaikul, Ani and Matsuda, Koichi and Mohlke, Karen L and Mononen, Nina and Murakami, Yoshinori and Nadkarni, Girish N and Nikus, Kjell and Pankratz, Nathan and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Raitakari, Olli T and Rich, Stephen S and Rodriguez, Benjamin A T and Rosen, Jonathan D and Rotter, Jerome I and Schubert, Petra and Spracklen, Cassandra N and Surendran, Praveen and Tang, Hua and Tardif, Jean-Claude and Ghanbari, Mohsen and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Watkins, Nicholas A and Weiss, Stefan and Cai, Na and Kundu, Kousik and Watt, Stephen B and Walter, Klaudia and Zonderman, Alan B and Cho, Kelly and Li, Yun and Loos, Ruth J F and Knight, Julian C and Georges, Michel and Stegle, Oliver and Evangelou, Evangelos and Okada, Yukinori and Roberts, David J and Inouye, Michael and Johnson, Andrew D and Auer, Paul L and Astle, William J and Reiner, Alexander P and Butterworth, Adam S and Ouwehand, Willem H and Lettre, Guillaume and Sankaran, Vijay G and Soranzo, Nicole} } @article {8481, title = {Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.}, journal = {Cell}, volume = {182}, year = {2020}, month = {2020 Sep 03}, pages = {1198-1213.e14}, abstract = {

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

}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.06.045}, author = {Chen, Ming-Huei and Raffield, Laura M and Mousas, Abdou and Sakaue, Saori and Huffman, Jennifer E and Moscati, Arden and Trivedi, Bhavi and Jiang, Tao and Akbari, Parsa and Vuckovic, Dragana and Bao, Erik L and Zhong, Xue and Manansala, Regina and Laplante, V{\'e}ronique and Chen, Minhui and Lo, Ken Sin and Qian, Huijun and Lareau, Caleb A and Beaudoin, M{\'e}lissa and Hunt, Karen A and Akiyama, Masato and Bartz, Traci M and Ben-Shlomo, Yoav and Beswick, Andrew and Bork-Jensen, Jette and Bottinger, Erwin P and Brody, Jennifer A and van Rooij, Frank J A and Chitrala, Kumaraswamynaidu and Cho, Kelly and Choquet, Helene and Correa, Adolfo and Danesh, John and Di Angelantonio, Emanuele and Dimou, Niki and Ding, Jingzhong and Elliott, Paul and Esko, T{\~o}nu and Evans, Michele K and Floyd, James S and Broer, Linda and Grarup, Niels and Guo, Michael H and Greinacher, Andreas and Haessler, Jeff and Hansen, Torben and Howson, Joanna M M and Huang, Qin Qin and Huang, Wei and Jorgenson, Eric and Kacprowski, Tim and K{\"a}h{\"o}nen, Mika and Kamatani, Yoichiro and Kanai, Masahiro and Karthikeyan, Savita and Koskeridis, Fotis and Lange, Leslie A and Lehtim{\"a}ki, Terho and Lerch, Markus M and Linneberg, Allan and Liu, Yongmei and Lyytik{\"a}inen, Leo-Pekka and Manichaikul, Ani and Martin, Hilary C and Matsuda, Koichi and Mohlke, Karen L and Mononen, Nina and Murakami, Yoshinori and Nadkarni, Girish N and Nauck, Matthias and Nikus, Kjell and Ouwehand, Willem H and Pankratz, Nathan and Pedersen, Oluf and Preuss, Michael and Psaty, Bruce M and Raitakari, Olli T and Roberts, David J and Rich, Stephen S and Rodriguez, Benjamin A T and Rosen, Jonathan D and Rotter, Jerome I and Schubert, Petra and Spracklen, Cassandra N and Surendran, Praveen and Tang, Hua and Tardif, Jean-Claude and Trembath, Richard C and Ghanbari, Mohsen and V{\"o}lker, Uwe and V{\"o}lzke, Henry and Watkins, Nicholas A and Zonderman, Alan B and Wilson, Peter W F and Li, Yun and Butterworth, Adam S and Gauchat, Jean-Fran{\c c}ois and Chiang, Charleston W K and Li, Bingshan and Loos, Ruth J F and Astle, William J and Evangelou, Evangelos and van Heel, David A and Sankaran, Vijay G and Okada, Yukinori and Soranzo, Nicole and Johnson, Andrew D and Reiner, Alexander P and Auer, Paul L and Lettre, Guillaume} } @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} }