@article {6089, title = {Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation.}, journal = {Blood}, volume = {120}, year = {2012}, month = {2012 Dec 06}, pages = {4873-81}, abstract = {

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 {\texttimes} 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 {\texttimes} 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 {\texttimes} 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 {\texttimes} 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

}, keywords = {Adaptor Proteins, Signal Transducing, ARNTL Transcription Factors, ATPases Associated with Diverse Cellular Activities, Cell Line, Cell Line, Tumor, Cohort Studies, Coronary Artery Disease, Diabetes Mellitus, Type 2, Gene Expression Profiling, Gene Expression Regulation, Gene Frequency, Genome-Wide Association Study, Genotype, Humans, LIM Domain Proteins, Meta-Analysis as Topic, Monocytes, Mucin-3, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide, PPAR gamma, Proteasome Endopeptidase Complex, RNA Interference, Transcription Factors}, issn = {1528-0020}, doi = {10.1182/blood-2012-06-436188}, author = {Huang, Jie and Sabater-Lleal, Maria and Asselbergs, Folkert W and Tregouet, David and Shin, So-Youn and Ding, Jingzhong and Baumert, Jens and Oudot-Mellakh, Tiphaine and Folkersen, Lasse and Johnson, Andrew D and Smith, Nicholas L and Williams, Scott M and Ikram, Mohammad A and Kleber, Marcus E and Becker, Diane M and Truong, Vinh and Mychaleckyj, Josyf C and Tang, Weihong and Yang, Qiong and Sennblad, Bengt and Moore, Jason H and Williams, Frances M K and Dehghan, Abbas and Silbernagel, G{\"u}nther and Schrijvers, Elisabeth M C and Smith, Shelly and Karakas, Mahir and Tofler, Geoffrey H and Silveira, Angela and Navis, Gerjan J and Lohman, Kurt and Chen, Ming-Huei and Peters, Annette and Goel, Anuj and Hopewell, Jemma C and Chambers, John C and Saleheen, Danish and Lundmark, Per and Psaty, Bruce M and Strawbridge, Rona J and Boehm, Bernhard O and Carter, Angela M and Meisinger, Christa and Peden, John F and Bis, Joshua C and McKnight, Barbara and Ohrvik, John and Taylor, Kent and Franzosi, Maria Grazia and Seedorf, Udo and Collins, Rory and Franco-Cereceda, Anders and Syv{\"a}nen, Ann-Christine and Goodall, Alison H and Yanek, Lisa R and Cushman, Mary and M{\"u}ller-Nurasyid, Martina and Folsom, Aaron R and Basu, Saonli and Matijevic, Nena and van Gilst, Wiek H and Kooner, Jaspal S and Hofman, Albert and Danesh, John and Clarke, Robert and Meigs, James B and Kathiresan, Sekar and Reilly, Muredach P and Klopp, Norman and Harris, Tamara B and Winkelmann, Bernhard R and Grant, Peter J and Hillege, Hans L and Watkins, Hugh and Spector, Timothy D and Becker, Lewis C and Tracy, Russell P and M{\"a}rz, Winfried and Uitterlinden, Andr{\'e} G and Eriksson, Per and Cambien, Francois and Morange, Pierre-Emmanuel and Koenig, Wolfgang and Soranzo, Nicole and van der Harst, Pim and Liu, Yongmei and O{\textquoteright}Donnell, Christopher J and Hamsten, Anders} } @article {6287, title = {Genome-wide association of body fat distribution in African ancestry populations suggests new loci.}, journal = {PLoS Genet}, volume = {9}, year = {2013}, month = {2013}, pages = {e1003681}, abstract = {

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 {\texttimes} 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24{\texttimes}10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48{\texttimes}10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 {\texttimes} 10(-8); RREB1: p = 5.7 {\texttimes} 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

}, keywords = {Adiposity, African Continental Ancestry Group, Body Fat Distribution, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Obesity, Polymorphism, Single Nucleotide, Waist-Hip Ratio}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003681}, author = {Liu, Ching-Ti and Monda, Keri L and Taylor, Kira C and Lange, Leslie and Demerath, Ellen W and Palmas, Walter and Wojczynski, Mary K and Ellis, Jaclyn C and Vitolins, Mara Z and Liu, Simin and Papanicolaou, George J and Irvin, Marguerite R and Xue, Luting and Griffin, Paula J and Nalls, Michael A and Adeyemo, Adebowale and Liu, Jiankang and Li, Guo and Ruiz-Narvaez, Edward A and Chen, Wei-Min and Chen, Fang and Henderson, Brian E and Millikan, Robert C and Ambrosone, Christine B and Strom, Sara S and Guo, Xiuqing and Andrews, Jeanette S and Sun, Yan V and Mosley, Thomas H and Yanek, Lisa R and Shriner, Daniel and Haritunians, Talin and Rotter, Jerome I and Speliotes, Elizabeth K and Smith, Megan and Rosenberg, Lynn and Mychaleckyj, Josyf and Nayak, Uma and Spruill, Ida and Garvey, W Timothy and Pettaway, Curtis and Nyante, Sarah and Bandera, Elisa V and Britton, Angela F and Zonderman, Alan B and Rasmussen-Torvik, Laura J and Chen, Yii-Der Ida and Ding, Jingzhong and Lohman, Kurt and Kritchevsky, Stephen B and Zhao, Wei and Peyser, Patricia A and Kardia, Sharon L R and Kabagambe, Edmond and Broeckel, Ulrich and Chen, Guanjie and Zhou, Jie and Wassertheil-Smoller, Sylvia and Neuhouser, Marian L and Rampersaud, Evadnie and Psaty, Bruce and Kooperberg, Charles and Manson, JoAnn E and Kuller, Lewis H and Ochs-Balcom, Heather M and Johnson, Karen C and Sucheston, Lara and Ordovas, Jose M and Palmer, Julie R and Haiman, Christopher A and McKnight, Barbara and Howard, Barbara V and Becker, Diane M and Bielak, Lawrence F and Liu, Yongmei and Allison, Matthew A and Grant, Struan F A and Burke, Gregory L and Patel, Sanjay R and Schreiner, Pamela J and Borecki, Ingrid B and Evans, Michele K and Taylor, Herman and Sale, Mich{\`e}le M and Howard, Virginia and Carlson, Christopher S and Rotimi, Charles N and Cushman, Mary and Harris, Tamara B and Reiner, Alexander P and Cupples, L Adrienne and North, Kari E and Fox, Caroline S} } @article {6078, title = {A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Jun}, pages = {690-6}, abstract = {

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of >3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 {\texttimes} 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 {\texttimes} 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 {\texttimes} 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 {\texttimes} 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

}, keywords = {African Americans, Body Mass Index, Case-Control Studies, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Obesity, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.2608}, author = {Monda, Keri L and Chen, Gary K and Taylor, Kira C and Palmer, Cameron and Edwards, Todd L and Lange, Leslie A and Ng, Maggie C Y and Adeyemo, Adebowale A and Allison, Matthew A and Bielak, Lawrence F and Chen, Guanjie and Graff, Mariaelisa and Irvin, Marguerite R and Rhie, Suhn K and Li, Guo and Liu, Yongmei and Liu, Youfang and Lu, Yingchang and Nalls, Michael A and Sun, Yan V and Wojczynski, Mary K and Yanek, Lisa R and Aldrich, Melinda C and Ademola, Adeyinka and Amos, Christopher I and Bandera, Elisa V and Bock, Cathryn H and Britton, Angela and Broeckel, Ulrich and Cai, Quiyin and Caporaso, Neil E and Carlson, Chris S and Carpten, John and Casey, Graham and Chen, Wei-Min and Chen, Fang and Chen, Yii-der I and Chiang, Charleston W K and Coetzee, Gerhard A and Demerath, Ellen and Deming-Halverson, Sandra L and Driver, Ryan W and Dubbert, Patricia and Feitosa, Mary F and Feng, Ye and Freedman, Barry I and Gillanders, Elizabeth M and Gottesman, Omri and Guo, Xiuqing and Haritunians, Talin and Harris, Tamara and Harris, Curtis C and Hennis, Anselm J M and Hernandez, Dena G and McNeill, Lorna H and Howard, Timothy D and Howard, Barbara V and Howard, Virginia J and Johnson, Karen C and Kang, Sun J and Keating, Brendan J and Kolb, Suzanne and Kuller, Lewis H and Kutlar, Abdullah and Langefeld, Carl D and Lettre, Guillaume and Lohman, Kurt and Lotay, Vaneet and Lyon, Helen and Manson, JoAnn E and Maixner, William and Meng, Yan A and Monroe, Kristine R and Morhason-Bello, Imran and Murphy, Adam B and Mychaleckyj, Josyf C and Nadukuru, Rajiv and Nathanson, Katherine L and Nayak, Uma and N{\textquoteright}diaye, Amidou and Nemesure, Barbara and Wu, Suh-Yuh and Leske, M Cristina and Neslund-Dudas, Christine and Neuhouser, Marian and Nyante, Sarah and Ochs-Balcom, Heather and Ogunniyi, Adesola and Ogundiran, Temidayo O and Ojengbede, Oladosu and Olopade, Olufunmilayo I and Palmer, Julie R and Ruiz-Narvaez, Edward A and Palmer, Nicholette D and Press, Michael F and Rampersaud, Evandine and Rasmussen-Torvik, Laura J and Rodriguez-Gil, Jorge L and Salako, Babatunde and Schadt, Eric E and Schwartz, Ann G and Shriner, Daniel A and Siscovick, David and Smith, Shad B and Wassertheil-Smoller, Sylvia and Speliotes, Elizabeth K and Spitz, Margaret R and Sucheston, Lara and Taylor, Herman and Tayo, Bamidele O and Tucker, Margaret A and Van Den Berg, David J and Edwards, Digna R Velez and Wang, Zhaoming and Wiencke, John K and Winkler, Thomas W and Witte, John S and Wrensch, Margaret and Wu, Xifeng and Yang, James J and Levin, Albert M and Young, Taylor R and Zakai, Neil A and Cushman, Mary and Zanetti, Krista A and Zhao, Jing Hua and Zhao, Wei and Zheng, Yonglan and Zhou, Jie and Ziegler, Regina G and Zmuda, Joseph M and Fernandes, Jyotika K and Gilkeson, Gary S and Kamen, Diane L and Hunt, Kelly J and Spruill, Ida J and Ambrosone, Christine B and Ambs, Stefan and Arnett, Donna K and Atwood, Larry and Becker, Diane M and Berndt, Sonja I and Bernstein, Leslie and Blot, William J and Borecki, Ingrid B and Bottinger, Erwin P and Bowden, Donald W and Burke, Gregory and Chanock, Stephen J and Cooper, Richard S and Ding, Jingzhong and Duggan, David and Evans, Michele K and Fox, Caroline and Garvey, W Timothy and Bradfield, Jonathan P and Hakonarson, Hakon and Grant, Struan F A and Hsing, Ann and Chu, Lisa and Hu, Jennifer J and Huo, Dezheng and Ingles, Sue A and John, Esther M and Jordan, Joanne M and Kabagambe, Edmond K and Kardia, Sharon L R and Kittles, Rick A and Goodman, Phyllis J and Klein, Eric A and Kolonel, Laurence N and Le Marchand, Lo{\"\i}c and Liu, Simin and McKnight, Barbara and Millikan, Robert C and Mosley, Thomas H and Padhukasahasram, Badri and Williams, L Keoki and Patel, Sanjay R and Peters, Ulrike and Pettaway, Curtis A and Peyser, Patricia A and Psaty, Bruce M and Redline, Susan and Rotimi, Charles N and Rybicki, Benjamin A and Sale, Mich{\`e}le M and Schreiner, Pamela J and Signorello, Lisa B and Singleton, Andrew B and Stanford, Janet L and Strom, Sara S and Thun, Michael J and Vitolins, Mara and Zheng, Wei and Moore, Jason H and Williams, Scott M and Ketkar, Shamika and Zhu, Xiaofeng and Zonderman, Alan B and Kooperberg, Charles and Papanicolaou, George J and Henderson, Brian E and Reiner, Alex P and Hirschhorn, Joel N and Loos, Ruth J F and North, Kari E and Haiman, Christopher A} } @article {6155, title = {Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease.}, journal = {Circulation}, volume = {128}, year = {2013}, month = {2013 Sep 17}, pages = {1310-24}, abstract = {

BACKGROUND: Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34\% to 50\%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (<2\%) of its variation.

METHODS AND RESULTS: We conducted a meta-analysis of 28 genome-wide association studies including >90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5{\texttimes}10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7\% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.

CONCLUSIONS: We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.

}, keywords = {Adolescent, Adult, African Continental Ancestry Group, Aged, Aged, 80 and over, Cardiovascular Diseases, Coronary Artery Disease, European Continental Ancestry Group, Female, Fibrinogen, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic Americans, Humans, Male, Middle Aged, Myocardial Infarction, Polymorphism, Single Nucleotide, Risk Factors, Stroke, Venous Thromboembolism, Young Adult}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.113.002251}, author = {Sabater-Lleal, Maria and Huang, Jie and Chasman, Daniel and Naitza, Silvia and Dehghan, Abbas and Johnson, Andrew D and Teumer, Alexander and Reiner, Alex P and Folkersen, Lasse and Basu, Saonli and Rudnicka, Alicja R and Trompet, Stella and M{\"a}larstig, Anders and Baumert, Jens and Bis, Joshua C and Guo, Xiuqing and Hottenga, Jouke J and Shin, So-Youn and Lopez, Lorna M and Lahti, Jari and Tanaka, Toshiko and Yanek, Lisa R and Oudot-Mellakh, Tiphaine and Wilson, James F and Navarro, Pau and Huffman, Jennifer E and Zemunik, Tatijana and Redline, Susan and Mehra, Reena and Pulanic, Drazen and Rudan, Igor and Wright, Alan F and Kolcic, Ivana and Polasek, Ozren and Wild, Sarah H and Campbell, Harry and Curb, J David and Wallace, Robert and Liu, Simin and Eaton, Charles B and Becker, Diane M and Becker, Lewis C and Bandinelli, Stefania and R{\"a}ikk{\"o}nen, Katri and Widen, Elisabeth and Palotie, Aarno and Fornage, Myriam and Green, David and Gross, Myron and Davies, Gail and Harris, Sarah E and Liewald, David C and Starr, John M and Williams, Frances M K and Grant, Peter J and Spector, Timothy D and Strawbridge, Rona J and Silveira, Angela and Sennblad, Bengt and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Franco, Oscar H and Hofman, Albert and van Dongen, Jenny and Willemsen, Gonneke and Boomsma, Dorret I and Yao, Jie and Swords Jenny, Nancy and Haritunians, Talin and McKnight, Barbara and Lumley, Thomas and Taylor, Kent D and Rotter, Jerome I and Psaty, Bruce M and Peters, Annette and Gieger, Christian and Illig, Thomas and Grotevendt, Anne and Homuth, Georg and V{\"o}lzke, Henry and Kocher, Thomas and Goel, Anuj and Franzosi, Maria Grazia and Seedorf, Udo and Clarke, Robert and Steri, Maristella and Tarasov, Kirill V and Sanna, Serena and Schlessinger, David and Stott, David J and Sattar, Naveed and Buckley, Brendan M and Rumley, Ann and Lowe, Gordon D and McArdle, Wendy L and Chen, Ming-Huei and Tofler, Geoffrey H and Song, Jaejoon and Boerwinkle, Eric and Folsom, Aaron R and Rose, Lynda M and Franco-Cereceda, Anders and Teichert, Martina and Ikram, M Arfan and Mosley, Thomas H and Bevan, Steve and Dichgans, Martin and Rothwell, Peter M and Sudlow, Cathie L M and Hopewell, Jemma C and Chambers, John C and Saleheen, Danish and Kooner, Jaspal S and Danesh, John and Nelson, Christopher P and Erdmann, Jeanette and Reilly, Muredach P and Kathiresan, Sekar and Schunkert, Heribert and Morange, Pierre-Emmanuel and Ferrucci, Luigi and Eriksson, Johan G and Jacobs, David and Deary, Ian J and Soranzo, Nicole and Witteman, Jacqueline C M and de Geus, Eco J C and Tracy, Russell P and Hayward, Caroline and Koenig, Wolfgang and Cucca, Francesco and Jukema, J Wouter and Eriksson, Per and Seshadri, Sudha and Markus, Hugh S and Watkins, Hugh and Samani, Nilesh J and Wallaschofski, Henri and Smith, Nicholas L and Tregouet, David and Ridker, Paul M and Tang, Weihong and Strachan, David P and Hamsten, Anders and O{\textquoteright}Donnell, Christopher J} } @article {6367, title = {Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {34}, year = {2014}, month = {2014 May}, pages = {1093-101}, abstract = {

OBJECTIVE: Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA.

APPROACH AND RESULTS: Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels (P<5.0{\texttimes}10(-8)). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P=2.9{\texttimes}10(-14)) within STXBP5. The second locus is on 8p11.21. The lead SNP (rs3136739; P=1.3{\texttimes}10(-9)) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT. We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 (r(2)=0.50) within exon 5 of PLAT (P=2.0{\texttimes}10(-8)). The third locus is on 12q24.33, with the lead SNP (rs7301826; P=1.0{\texttimes}10(-9)) within intron 7 of STX2. We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke.

CONCLUSIONS: We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5, and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release.

}, keywords = {Aged, Cells, Cultured, Coronary Artery Disease, Endothelial Cells, Europe, Female, Gene Expression Regulation, Gene Silencing, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Phenotype, Polymorphism, Single Nucleotide, R-SNARE Proteins, Risk Factors, Stroke, Syntaxin 1, Tissue Plasminogen Activator, Transfection, United States, Up-Regulation}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.113.302088}, author = {Huang, Jie and Huffman, Jennifer E and Yamakuchi, Munekazu and Yamkauchi, Munekazu and Trompet, Stella and Asselbergs, Folkert W and Sabater-Lleal, Maria and Tr{\'e}gou{\"e}t, David-Alexandre and Chen, Wei-Min and Smith, Nicholas L and Kleber, Marcus E and Shin, So-Youn and Becker, Diane M and Tang, Weihong and Dehghan, Abbas and Johnson, Andrew D and Truong, Vinh and Folkersen, Lasse and Yang, Qiong and Oudot-Mellkah, Tiphaine and Buckley, Brendan M and Moore, Jason H and Williams, Frances M K and Campbell, Harry and Silbernagel, G{\"u}nther and Vitart, Veronique and Rudan, Igor and Tofler, Geoffrey H and Navis, Gerjan J and DeStefano, Anita and Wright, Alan F and Chen, Ming-Huei and de Craen, Anton J M and Worrall, Bradford B and Rudnicka, Alicja R and Rumley, Ann and Bookman, Ebony B and Psaty, Bruce M and Chen, Fang and Keene, Keith L and Franco, Oscar H and B{\"o}hm, Bernhard O and Uitterlinden, Andr{\'e} G and Carter, Angela M and Jukema, J Wouter and Sattar, Naveed and Bis, Joshua C and Ikram, Mohammad A and Sale, Mich{\`e}le M and McKnight, Barbara and Fornage, Myriam and Ford, Ian and Taylor, Kent and Slagboom, P Eline and McArdle, Wendy L and Hsu, Fang-Chi and Franco-Cereceda, Anders and Goodall, Alison H and Yanek, Lisa R and Furie, Karen L and Cushman, Mary and Hofman, Albert and Witteman, Jacqueline C M and Folsom, Aaron R and Basu, Saonli and Matijevic, Nena and van Gilst, Wiek H and Wilson, James F and Westendorp, Rudi G J and Kathiresan, Sekar and Reilly, Muredach P and Tracy, Russell P and Polasek, Ozren and Winkelmann, Bernhard R and Grant, Peter J and Hillege, Hans L and Cambien, Francois and Stott, David J and Lowe, Gordon D and Spector, Timothy D and Meigs, James B and M{\"a}rz, Winfried and Eriksson, Per and Becker, Lewis C and Morange, Pierre-Emmanuel and Soranzo, Nicole and Williams, Scott M and Hayward, Caroline and van der Harst, Pim and Hamsten, Anders and Lowenstein, Charles J and Strachan, David P and O{\textquoteright}Donnell, Christopher J} } @article {6585, title = {Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.}, journal = {PLoS Genet}, volume = {10}, year = {2014}, month = {2014 Aug}, pages = {e1004517}, abstract = {

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 {\texttimes} 10(-94)}, keywords = {African Americans, Diabetes Mellitus, Type 2, Genome-Wide Association Study, HLA-B27 Antigen, HMGA2 Protein, Humans, KCNQ1 Potassium Channel, Mutant Chimeric Proteins, Polymorphism, Single Nucleotide, Transcription Factor 7-Like 2 Protein}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004517}, author = {Ng, Maggie C Y and Shriner, Daniel and Chen, Brian H and Li, Jiang and Chen, Wei-Min and Guo, Xiuqing and Liu, Jiankang and Bielinski, Suzette J and Yanek, Lisa R and Nalls, Michael A and Comeau, Mary E and Rasmussen-Torvik, Laura J and Jensen, Richard A and Evans, Daniel S and Sun, Yan V and An, Ping and Patel, Sanjay R and Lu, Yingchang and Long, Jirong and Armstrong, Loren L and Wagenknecht, Lynne and Yang, Lingyao and Snively, Beverly M and Palmer, Nicholette D and Mudgal, Poorva and Langefeld, Carl D and Keene, Keith L and Freedman, Barry I and Mychaleckyj, Josyf C and Nayak, Uma and Raffel, Leslie J and Goodarzi, Mark O and Chen, Y-D Ida and Taylor, Herman A and Correa, Adolfo and Sims, Mario and Couper, David and Pankow, James S and Boerwinkle, Eric and Adeyemo, Adebowale and Doumatey, Ayo and Chen, Guanjie and Mathias, Rasika A and Vaidya, Dhananjay and Singleton, Andrew B and Zonderman, Alan B and Igo, Robert P and Sedor, John R and Kabagambe, Edmond K and Siscovick, David S and McKnight, Barbara and Rice, Kenneth and Liu, Yongmei and Hsueh, Wen-Chi and Zhao, Wei and Bielak, Lawrence F and Kraja, Aldi and Province, Michael A and Bottinger, Erwin P and Gottesman, Omri and Cai, Qiuyin and Zheng, Wei and Blot, William J and Lowe, William L and Pacheco, Jennifer A and Crawford, Dana C and Grundberg, Elin and Rich, Stephen S and Hayes, M Geoffrey and Shu, Xiao-Ou and Loos, Ruth J F and Borecki, Ingrid B and Peyser, Patricia A and Cummings, Steven R and Psaty, Bruce M and Fornage, Myriam and Iyengar, Sudha K and Evans, Michele K and Becker, Diane M and Kao, W H Linda and Wilson, James G and Rotter, Jerome I and Sale, Mich{\`e}le M and Liu, Simin and Rotimi, Charles N and Bowden, Donald W} } @article {6573, title = {Trans-ethnic meta-analysis of white blood cell phenotypes.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Dec 20}, pages = {6944-60}, abstract = {

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool.

}, keywords = {African Americans, Asian Continental Ancestry Group, Bayes Theorem, European Continental Ancestry Group, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Leukocyte Count, Leukocytes, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1460-2083}, doi = {10.1093/hmg/ddu401}, author = {Keller, Margaux F and Reiner, Alexander P and Okada, Yukinori and van Rooij, Frank J A and Johnson, Andrew D and Chen, Ming-Huei and Smith, Albert V and Morris, Andrew P and Tanaka, Toshiko and Ferrucci, Luigi and Zonderman, Alan B and Lettre, Guillaume and Harris, Tamara and Garcia, Melissa and Bandinelli, Stefania and Qayyum, Rehan and Yanek, Lisa R and Becker, Diane M and Becker, Lewis C and Kooperberg, Charles and Keating, Brendan and Reis, Jared and Tang, Hua and Boerwinkle, Eric and Kamatani, Yoichiro and Matsuda, Koichi and Kamatani, Naoyuki and Nakamura, Yusuke and Kubo, Michiaki and Liu, Simin and Dehghan, Abbas and Felix, Janine F and Hofman, Albert and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Franco, Oscar H and Longo, Dan L and Singleton, Andrew B and Psaty, Bruce M and Evans, Michelle K and Cupples, L Adrienne and Rotter, Jerome I and O{\textquoteright}Donnell, Christopher J and Takahashi, Atsushi and Wilson, James G and Ganesh, Santhi K and Nalls, Mike A} } @article {7572, title = {Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 May}, pages = {e1006728}, abstract = {

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25{\texttimes}10-8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

}, keywords = {African Americans, Animals, Basic Helix-Loop-Helix Transcription Factors, Blood Pressure, Cadherins, Case-Control Studies, Female, Genetic Loci, Genome-Wide Association Study, Humans, Hypertension, Male, Membrane Proteins, Mice, Multifactorial Inheritance, Polymorphism, Single Nucleotide}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006728}, author = {Liang, Jingjing and Le, Thu H and Edwards, Digna R Velez and Tayo, Bamidele O and Gaulton, Kyle J and Smith, Jennifer A and Lu, Yingchang and Jensen, Richard A and Chen, Guanjie and Yanek, Lisa R and Schwander, Karen and Tajuddin, Salman M and Sofer, Tamar and Kim, Wonji and Kayima, James and McKenzie, Colin A and Fox, Ervin and Nalls, Michael A and Young, J Hunter and Sun, Yan V and Lane, Jacqueline M and Cechova, Sylvia and Zhou, Jie and Tang, Hua and Fornage, Myriam and Musani, Solomon K and Wang, Heming and Lee, Juyoung and Adeyemo, Adebowale and Dreisbach, Albert W and Forrester, Terrence and Chu, Pei-Lun and Cappola, Anne and Evans, Michele K and Morrison, Alanna C and Martin, Lisa W and Wiggins, Kerri L and Hui, Qin and Zhao, Wei and Jackson, Rebecca D and Ware, Erin B and Faul, Jessica D and Reiner, Alex P and Bray, Michael and Denny, Joshua C and Mosley, Thomas H and Palmas, Walter and Guo, Xiuqing and Papanicolaou, George J and Penman, Alan D and Polak, Joseph F and Rice, Kenneth and Taylor, Ken D and Boerwinkle, Eric and Bottinger, Erwin P and Liu, Kiang and Risch, Neil and Hunt, Steven C and Kooperberg, Charles and Zonderman, Alan B and Laurie, Cathy C and Becker, Diane M and Cai, Jianwen and Loos, Ruth J F and Psaty, Bruce M and Weir, David R and Kardia, Sharon L R and Arnett, Donna K and Won, Sungho and Edwards, Todd L and Redline, Susan and Cooper, Richard S and Rao, D C and Rotter, Jerome I and Rotimi, Charles and Levy, Daniel and Chakravarti, Aravinda and Zhu, Xiaofeng and Franceschini, Nora} } @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 {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 {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 {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 {9104, title = {Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.}, journal = {Nat Genet}, volume = {54}, year = {2022}, month = {2022 May}, pages = {560-572}, abstract = {

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

}, keywords = {Diabetes Mellitus, Type 2, Ethnicity, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Risk Factors}, issn = {1546-1718}, doi = {10.1038/s41588-022-01058-3}, author = {Mahajan, Anubha and Spracklen, Cassandra N and Zhang, Weihua and Ng, Maggie C Y and Petty, Lauren E and Kitajima, Hidetoshi and Yu, Grace Z and R{\"u}eger, Sina and Speidel, Leo and Kim, Young Jin and Horikoshi, Momoko and Mercader, Josep M and Taliun, Daniel and Moon, Sanghoon and Kwak, Soo-Heon and Robertson, Neil R and Rayner, Nigel W and Loh, Marie and Kim, Bong-Jo and Chiou, Joshua and Miguel-Escalada, Irene and Della Briotta Parolo, Pietro and Lin, Kuang and Bragg, Fiona and Preuss, Michael H and Takeuchi, Fumihiko and Nano, Jana and Guo, Xiuqing and Lamri, Amel and Nakatochi, Masahiro and Scott, Robert A and Lee, Jung-Jin and Huerta-Chagoya, Alicia and Graff, Mariaelisa and Chai, Jin-Fang and Parra, Esteban J and Yao, Jie and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Steinthorsdottir, Valgerdur and Cook, James P and Kals, Mart and Grarup, Niels and Schmidt, Ellen M and Pan, Ian and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Ahmad, Meraj and Noordam, Raymond and Lim, Victor J Y and Tam, Claudia H T and Joo, Yoonjung Yoonie and Chen, Chien-Hsiun and Raffield, Laura M and Lecoeur, C{\'e}cile and Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Jensen, Richard A and Tajuddin, Salman and Kabagambe, Edmond K and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Flanagan, Jack and Abaitua, Fernando and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Akiyama, Masato and Anand, Sonia S and Bertoni, Alain and Bian, Zheng and Bork-Jensen, Jette and Brandslund, Ivan and Brody, Jennifer A and Brummett, Chad M and Buchanan, Thomas A and Canouil, Micka{\"e}l and Chan, Juliana C N and Chang, Li-Ching and Chee, Miao-Li and Chen, Ji and Chen, Shyh-Huei and Chen, Yuan-Tsong and Chen, Zhengming and Chuang, Lee-Ming and Cushman, Mary and Das, Swapan K and de Silva, H Janaka and Dedoussis, George and Dimitrov, Latchezar and Doumatey, Ayo P and Du, Shufa and Duan, Qing and Eckardt, Kai-Uwe and Emery, Leslie S and Evans, Daniel S and Evans, Michele K and Fischer, Krista and Floyd, James S and Ford, Ian and Fornage, Myriam and Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Fuchsberger, Christian and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Goodarzi, Mark O and Gordon-Larsen, Penny and Gorkin, David and Gross, Myron and Guo, Yu and Hackinger, Sophie and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Howard, Annie-Green and Hsueh, Willa and Huang, Mengna and Huang, Wei and Hung, Yi-Jen and Hwang, Mi Yeong and Hwu, Chii-Min and Ichihara, Sahoko and Ikram, Mohammad Arfan and Ingelsson, Martin and Islam, Md Tariqul and Isono, Masato and Jang, Hye-Mi and Jasmine, Farzana and Jiang, Guozhi and Jonas, Jost B and J{\o}rgensen, Marit E and J{\o}rgensen, Torben and Kamatani, Yoichiro and Kandeel, Fouad R and Kasturiratne, Anuradhani and Katsuya, Tomohiro and Kaur, Varinderpal and Kawaguchi, Takahisa and Keaton, Jacob M and Kho, Abel N and Khor, Chiea-Chuen and Kibriya, Muhammad G and Kim, Duk-Hwan and Kohara, Katsuhiko and Kriebel, Jennifer and Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Myung-Shik and Lee, Nanette R and Leong, Aaron and Li, Liming and Li, Yun and Li-Gao, Ruifang and Ligthart, Symen and Lindgren, Cecilia M and Linneberg, Allan and Liu, Ching-Ti and Liu, Jianjun and Locke, Adam E and Louie, Tin and Luan, Jian{\textquoteright}an and Luk, Andrea O and Luo, Xi and Lv, Jun and Lyssenko, Valeriya and Mamakou, Vasiliki and Mani, K Radha and Meitinger, Thomas and Metspalu, Andres and Morris, Andrew D and Nadkarni, Girish N and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Nongmaithem, Suraj S and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Porneala, Bianca and Prasad, Gauri and Preissl, Sebastian and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Kathryn and Sabanayagam, Charumathi and Sander, Maike and Sandow, Kevin and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Schurmann, Claudia and Shahriar, Mohammad and Shi, Jinxiu and Shin, Dong Mun and Shriner, Daniel and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Stilp, Adrienne M and Strauch, Konstantin and Suzuki, Ken and Takahashi, Atsushi and Taylor, Kent D and Thorand, Barbara and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tomlinson, Brian and Torres, Jason M and Tsai, Fuu-Jen and Tuomilehto, Jaakko and Tusi{\'e}-Luna, Teresa and Udler, Miriam S and Valladares-Salgado, Adan and van Dam, Rob M and van Klinken, Jan B and Varma, Rohit and Vujkovic, Marijana and Wacher-Rodarte, Niels and Wheeler, Eleanor and Whitsel, Eric A and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamauchi, Toshimasa and Yengo, Loic and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zhang, Liang and Zheng, Wei and Raffel, Leslie J and Igase, Michiya and Ipp, Eli and Redline, Susan and Cho, Yoon Shin and Lind, Lars and Province, Michael A and Hanis, Craig L and Peyser, Patricia A and Ingelsson, Erik and Zonderman, Alan B and Psaty, Bruce M and Wang, Ya-Xing and Rotimi, Charles N and Becker, Diane M and Matsuda, Fumihiko and Liu, Yongmei and Zeggini, Eleftheria and Yokota, Mitsuhiro and Rich, Stephen S and Kooperberg, Charles and Pankow, James S and Engert, James C and Chen, Yii-Der Ida and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Kardia, Sharon L R and Wu, Jer-Yuarn and Hayes, M Geoffrey and Ma, Ronald C W and Wong, Tien-Yin and Groop, Leif and Mook-Kanamori, Dennis O and Chandak, Giriraj R and Collins, Francis S and Bharadwaj, Dwaipayan and Par{\'e}, Guillaume and Sale, Mich{\`e}le M and Ahsan, Habibul and Motala, Ayesha A and Shu, Xiao-Ou and Park, Kyong-Soo and Jukema, J Wouter and Cruz, Miguel and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Bottinger, Erwin P and Dehghan, Abbas and Tai, E-Shyong and Dupuis, Jos{\'e}e and Kato, Norihiro and Laakso, Markku and K{\"o}ttgen, Anna and Koh, Woon-Puay and Palmer, Colin N A and Liu, Simin and Abecasis, Goncalo and Kooner, Jaspal S and Loos, Ruth J F and North, Kari E and Haiman, Christopher A and Florez, Jose C and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and M{\"a}gi, Reedik and Langenberg, Claudia and Wareham, Nicholas J and Maeda, Shiro and Kadowaki, Takashi and Lee, Juyoung and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Myers, Simon R and Ferrer, Jorge and Gaulton, Kyle J and Meigs, James B and Mohlke, Karen L and Gloyn, Anna L and Bowden, Donald W and Below, Jennifer E and Chambers, John C and Sim, Xueling and Boehnke, Michael and Rotter, Jerome I and McCarthy, Mark I and Morris, Andrew P} } @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 {9109, title = {The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations.}, journal = {Front Endocrinol (Lausanne)}, volume = {13}, year = {2022}, month = {2022}, pages = {863893}, abstract = {

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) >=1\%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRS) with a rare variant PRS (PRS) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m), obesity (BMI >= 30 kg/m), and extreme obesity (BMI >= 40 kg/m). We built PRSs and PRSs using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRS explained 10.1\% of variation in BMI, and 18.3\% and 22.5\% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRS explained 1.49\%, and 2.97\% and 3.68\%, respectively. The PRS was associated with an increased risk of obesity and extreme obesity (OR = 1.37 per SD, = 1.7x10; OR = 1.55 per SD, = 3.8x10), which was attenuated, after adjusting for PRS (OR = 1.08 per SD, = 9.8x10; OR= 1.09 per SD, = 0.02). When PRS and PRS are combined, the increase in explained variance attributed to PRS was small (incremental Nagelkerke R = 0.24\% for obesity and 0.51\% for extreme obesity). Consistently, combining PRS to PRS provided little improvement to the prediction of obesity (PRS AUC = 0.591; PRS AUC = 0.708; PRS AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRS provides limited improvement over PRS in the prediction of obesity risk, based on these large populations.

}, keywords = {Gene Frequency, Genetic Variation, Genome-Wide Association Study, Humans, Obesity, Whole Genome Sequencing}, issn = {1664-2392}, doi = {10.3389/fendo.2022.863893}, author = {Wang, Zhe and Choi, Shing Wan and Chami, Nathalie and Boerwinkle, Eric and Fornage, Myriam and Redline, Susan and Bis, Joshua C and Brody, Jennifer A and Psaty, Bruce M and Kim, Wonji and McDonald, Merry-Lynn N and Regan, Elizabeth A and Silverman, Edwin K and Liu, Ching-Ti and Vasan, Ramachandran S and Kalyani, Rita R and Mathias, Rasika A and Yanek, Lisa R and Arnett, Donna K and Justice, Anne E and North, Kari E and Kaplan, Robert and Heckbert, Susan R and de Andrade, Mariza and Guo, Xiuqing and Lange, Leslie A and Rich, Stephen S and Rotter, Jerome I and Ellinor, Patrick T and Lubitz, Steven A and Blangero, John and Shoemaker, M Benjamin and Darbar, Dawood and Gladwin, Mark T and Albert, Christine M and Chasman, Daniel I and Jackson, Rebecca D and Kooperberg, Charles and Reiner, Alexander P and O{\textquoteright}Reilly, Paul F and Loos, Ruth J F} } @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 {9387, title = {Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.}, journal = {Nature}, volume = {616}, year = {2023}, month = {2023 Apr}, pages = {755-763}, abstract = {

Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis. These lesions are precursors for blood cancers, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but~this effect was not seen in~clones with~driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental~knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

}, keywords = {Alleles, Animals, Clonal Hematopoiesis, Genome-Wide Association Study, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mice, Mutation, Promoter Regions, Genetic}, issn = {1476-4687}, doi = {10.1038/s41586-023-05806-1}, author = {Weinstock, Joshua S and Gopakumar, Jayakrishnan and Burugula, Bala Bharathi and Uddin, Md Mesbah and Jahn, Nikolaus and Belk, Julia A and Bouzid, Hind and Daniel, Bence and Miao, Zhuang and Ly, Nghi and Mack, Taralynn M and Luna, Sofia E and Prothro, Katherine P and Mitchell, Shaneice R and Laurie, Cecelia A and Broome, Jai G and Taylor, Kent D and Guo, Xiuqing and Sinner, Moritz F and von Falkenhausen, Aenne S and K{\"a}{\"a}b, Stefan and Shuldiner, Alan R and O{\textquoteright}Connell, Jeffrey R and Lewis, Joshua P and Boerwinkle, Eric and Barnes, Kathleen C and Chami, Nathalie and Kenny, Eimear E and Loos, Ruth J F and Fornage, Myriam and Hou, Lifang and Lloyd-Jones, Donald M and Redline, Susan and Cade, Brian E and Psaty, Bruce M and Bis, Joshua C and Brody, Jennifer A and Silverman, Edwin K and Yun, Jeong H and Qiao, Dandi and Palmer, Nicholette D and Freedman, Barry I and Bowden, Donald W and Cho, Michael H and DeMeo, Dawn L and Vasan, Ramachandran S and Yanek, Lisa R and Becker, Lewis C and Kardia, Sharon L R and Peyser, Patricia A and He, Jiang and Rienstra, Michiel and van der Harst, Pim and Kaplan, Robert and Heckbert, Susan R and Smith, Nicholas L and Wiggins, Kerri L and Arnett, Donna K and Irvin, Marguerite R and Tiwari, Hemant and Cutler, Michael J and Knight, Stacey and Muhlestein, J Brent and Correa, Adolfo and Raffield, Laura M and Gao, Yan and de Andrade, Mariza and Rotter, Jerome I and Rich, Stephen S and Tracy, Russell P and Konkle, Barbara A and Johnsen, Jill M and Wheeler, Marsha M and Smith, J Gustav and Melander, Olle and Nilsson, Peter M and Custer, Brian S and Duggirala, Ravindranath and Curran, Joanne E and Blangero, John and McGarvey, Stephen and Williams, L Keoki and Xiao, Shujie and Yang, Mao and Gu, C Charles and Chen, Yii-Der Ida and Lee, Wen-Jane and Marcus, Gregory M and Kane, John P and Pullinger, Clive R and Shoemaker, M Benjamin and Darbar, Dawood and Roden, Dan M and Albert, Christine and Kooperberg, Charles and Zhou, Ying and Manson, JoAnn E and Desai, Pinkal and Johnson, Andrew D and Mathias, Rasika A and Blackwell, Thomas W and Abecasis, Goncalo R and Smith, Albert V and Kang, Hyun M and Satpathy, Ansuman T and Natarajan, Pradeep and Kitzman, Jacob O and Whitsel, Eric A and Reiner, Alexander P and Bick, Alexander G and Jaiswal, Siddhartha} } @article {9412, title = {Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing.}, journal = {Nat Genet}, volume = {55}, year = {2023}, month = {2023 Feb}, pages = {291-300}, abstract = {

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55\% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction.

}, keywords = {Biology, Drug Repositioning, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Tobacco Use, Transcriptome}, issn = {1546-1718}, doi = {10.1038/s41588-022-01282-x}, author = {Chen, Fang and Wang, Xingyan and Jang, Seon-Kyeong and Quach, Bryan C and Weissenkampen, J Dylan and Khunsriraksakul, Chachrit and Yang, Lina and Sauteraud, Renan and Albert, Christine M and Allred, Nicholette D D and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Barr, R Graham and Becker, Diane M and Bielak, Lawrence F and Bis, Joshua C and Blangero, John and Boorgula, Meher Preethi and Chasman, Daniel I and Chavan, Sameer and Chen, Yii-der I and Chuang, Lee-Ming and Correa, Adolfo and Curran, Joanne E and David, Sean P and Fuentes, Lisa de Las and Deka, Ranjan and Duggirala, Ravindranath and Faul, Jessica D and Garrett, Melanie E and Gharib, Sina A and Guo, Xiuqing and Hall, Michael E and Hawley, Nicola L and He, Jiang and Hobbs, Brian D and Hokanson, John E and Hsiung, Chao A and Hwang, Shih-Jen and Hyde, Thomas M and Irvin, Marguerite R and Jaffe, Andrew E and Johnson, Eric O and Kaplan, Robert and Kardia, Sharon L R and Kaufman, Joel D and Kelly, Tanika N and Kleinman, Joel E and Kooperberg, Charles and Lee, I-Te and Levy, Daniel and Lutz, Sharon M and Manichaikul, Ani W and Martin, Lisa W and Marx, Olivia and McGarvey, Stephen T and Minster, Ryan L and Moll, Matthew and Moussa, Karine A and Naseri, Take and North, Kari E and Oelsner, Elizabeth C and Peralta, Juan M and Peyser, Patricia A and Psaty, Bruce M and Rafaels, Nicholas and Raffield, Laura M and Reupena, Muagututi{\textquoteright}a Sefuiva and Rich, Stephen S and Rotter, Jerome I and Schwartz, David A and Shadyab, Aladdin H and Sheu, Wayne H-H and Sims, Mario and Smith, Jennifer A and Sun, Xiao and Taylor, Kent D and Telen, Marilyn J and Watson, Harold and Weeks, Daniel E and Weir, David R and Yanek, Lisa R and Young, Kendra A and Young, Kristin L and Zhao, Wei and Hancock, Dana B and Jiang, Bibo and Vrieze, Scott and Liu, Dajiang J} } @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 {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 {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} } @article {9942, title = {Whole genome sequencing analysis of body mass index identifies novel African ancestry-specific risk allele.}, journal = {Nat Commun}, volume = {16}, year = {2025}, month = {2025 Apr 11}, pages = {3470}, abstract = {

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51\% were of non-European population groups. We discovered 18 BMI-associated signals (P < 5 {\texttimes} 10), including two secondary signals. Notably, we identified and replicated a novel low-frequency single nucleotide polymorphism (SNP) in MTMR3 that was common in individuals of African descent. Using a diverse study population, we further identified two novel secondary signals in known BMI loci and pinpointed two likely causal variants in the POC5 and DMD loci. Our work demonstrates the benefits of combining WGS and diverse cohorts in expanding current catalog of variants and genes confer risk for obesity, bringing us one step closer to personalized medicine.

}, keywords = {Adult, African People, Alleles, Body Mass Index, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Population Groups, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-025-58420-2}, author = {Zhang, Xinruo and Brody, Jennifer A and Graff, Mariaelisa and Highland, Heather M and Chami, Nathalie and Xu, Hanfei and Wang, Zhe and Ferrier, Kendra R and Chittoor, Geetha and Josyula, Navya Shilpa and Meyer, Mariah and Gupta, Shreyash and Li, Xihao and Li, Zilin and Allison, Matthew A and Becker, Diane M and Bielak, Lawrence F and Bis, Joshua C and Boorgula, Meher Preethi and Bowden, Donald W and Broome, Jai G and Buth, Erin J and Carlson, Christopher S and Chang, Kyong-Mi and Chavan, Sameer and Chiu, Yen-Feng and Chuang, Lee-Ming and Conomos, Matthew P and DeMeo, Dawn L and Du, Mengmeng and Duggirala, Ravindranath and Eng, Celeste and Fohner, Alison E and Freedman, Barry I and Garrett, Melanie E and Guo, Xiuqing and Haiman, Chris and Heavner, Benjamin D and Hidalgo, Bertha and Hixson, James E and Ho, Yuk-Lam and Hobbs, Brian D and Hu, Donglei and Hui, Qin and Hwu, Chii-Min and Jackson, Rebecca D and Jain, Deepti and Kalyani, Rita R and Kardia, Sharon L R and Kelly, Tanika N and Lange, Ethan M and LeNoir, Michael and Li, Changwei and Le Marchand, Lo{\"\i}c and McDonald, Merry-Lynn N and McHugh, Caitlin P and Morrison, Alanna C and Naseri, Take and O{\textquoteright}Connell, Jeffrey and O{\textquoteright}Donnell, Christopher J and Palmer, Nicholette D and Pankow, James S and Perry, James A and Peters, Ulrike and Preuss, Michael H and Rao, D C and Regan, Elizabeth A and Reupena, Sefuiva M and Roden, Dan M and Rodriguez-Santana, Jose and Sitlani, Colleen M and Smith, Jennifer A and Tiwari, Hemant K and Vasan, Ramachandran S and Wang, Zeyuan and Weeks, Daniel E and Wessel, Jennifer and Wiggins, Kerri L and Wilkens, Lynne R and Wilson, Peter W F and Yanek, Lisa R and Yoneda, Zachary T and Zhao, Wei and Z{\"o}llner, Sebastian and Arnett, Donna K and Ashley-Koch, Allison E and Barnes, Kathleen C and Blangero, John and Boerwinkle, Eric and Burchard, Esteban G and Carson, April P and Chasman, Daniel I and Ida Chen, Yii-Der and Curran, Joanne E and Fornage, Myriam and Gordeuk, Victor R and He, Jiang and Heckbert, Susan R and Hou, Lifang and Irvin, Marguerite R and Kooperberg, Charles and Minster, Ryan L and Mitchell, Braxton D and Nouraie, Mehdi and Psaty, Bruce M and Raffield, Laura M and Reiner, Alexander P and Rich, Stephen S and Rotter, Jerome I and Benjamin Shoemaker, M and Smith, Nicholas L and Taylor, Kent D and Telen, Marilyn J and Weiss, Scott T and Zhang, Yingze and Heard-Costa, Nancy and Sun, Yan V and Lin, Xihong and Cupples, L Adrienne and Lange, Leslie A and Liu, Ching-Ti and Loos, Ruth J F and North, Kari E and Justice, Anne E} }