@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 {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 {7141, title = {Trans-ethnic Meta-analysis and Functional Annotation Illuminates the~Genetic Architecture of Fasting Glucose and Insulin.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Jul 7}, pages = {56-75}, abstract = {

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.05.006}, author = {Liu, Ching-Ti and Raghavan, Sridharan and Maruthur, Nisa and Kabagambe, Edmond Kato and Hong, Jaeyoung and Ng, Maggie C Y and Hivert, Marie-France and Lu, Yingchang and An, Ping and Bentley, Amy R and Drolet, Anne M and Gaulton, Kyle J and Guo, Xiuqing and Armstrong, Loren L and Irvin, Marguerite R and Li, Man and Lipovich, Leonard and Rybin, Denis V and Taylor, Kent D and Agyemang, Charles and Palmer, Nicholette D and Cade, Brian E and Chen, Wei-Min and Dauriz, Marco and Delaney, Joseph A C and Edwards, Todd L and Evans, Daniel S and Evans, Michele K and Lange, Leslie A and Leong, Aaron and Liu, Jingmin and Liu, Yongmei and Nayak, Uma and Patel, Sanjay R and Porneala, Bianca C and Rasmussen-Torvik, Laura J and Snijder, Marieke B and Stallings, Sarah C and Tanaka, Toshiko and Yanek, Lisa R and Zhao, Wei and Becker, Diane M and Bielak, Lawrence F and Biggs, Mary L and Bottinger, Erwin P and Bowden, Donald W and Chen, Guanjie and Correa, Adolfo and Couper, David J and Crawford, Dana C and Cushman, Mary and Eicher, John D and Fornage, Myriam and Franceschini, Nora and Fu, Yi-Ping and Goodarzi, Mark O and Gottesman, Omri and Hara, Kazuo and Harris, Tamara B and Jensen, Richard A and Johnson, Andrew D and Jhun, Min A and Karter, Andrew J and Keller, Margaux F and Kho, Abel N and Kizer, Jorge R and Krauss, Ronald M and Langefeld, Carl D and Li, Xiaohui and Liang, Jingling and Liu, Simin and Lowe, William L and Mosley, Thomas H and North, Kari E and Pacheco, Jennifer A and Peyser, Patricia A and Patrick, Alan L and Rice, Kenneth M and Selvin, Elizabeth and Sims, Mario and Smith, Jennifer A and Tajuddin, Salman M and Vaidya, Dhananjay and Wren, Mary P and Yao, Jie and Zhu, Xiaofeng and Ziegler, Julie T and Zmuda, Joseph M and Zonderman, Alan B and Zwinderman, Aeilko H and Adeyemo, Adebowale and Boerwinkle, Eric and Ferrucci, Luigi and Hayes, M Geoffrey and Kardia, Sharon L R and Miljkovic, Iva and Pankow, James S and Rotimi, Charles N and Sale, Mich{\`e}le M and Wagenknecht, Lynne E and Arnett, Donna K and Chen, Yii-Der Ida and Nalls, Michael A and Province, Michael A and Kao, W H Linda and Siscovick, David S and Psaty, Bruce M and Wilson, James G and Loos, Ruth J F and Dupuis, Jos{\'e}e and Rich, Stephen S and Florez, Jose C and Rotter, Jerome I and Morris, Andrew P and Meigs, James B} } @article {7352, title = {Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African ancestry anthropometry genetics consortium.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 Apr 21}, pages = {e1006719}, abstract = {

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5{\texttimes}10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5\%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained <= 20 variants in the credible sets that jointly account for 99\% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006719}, author = {Ng, Maggie C Y and Graff, Mariaelisa and Lu, Yingchang and Justice, Anne E and Mudgal, Poorva and Liu, Ching-Ti and Young, Kristin and Yanek, Lisa R and Feitosa, Mary F and Wojczynski, Mary K and Rand, Kristin and Brody, Jennifer A and Cade, Brian E and Dimitrov, Latchezar and Duan, Qing and Guo, Xiuqing and Lange, Leslie A and Nalls, Michael A and Okut, Hayrettin and Tajuddin, Salman M and Tayo, Bamidele O and Vedantam, Sailaja and Bradfield, Jonathan P and Chen, Guanjie and Chen, Wei-Min and Chesi, Alessandra and Irvin, Marguerite R and Padhukasahasram, Badri and Smith, Jennifer A and Zheng, Wei and Allison, Matthew A and Ambrosone, Christine B and Bandera, Elisa V and Bartz, Traci M and Berndt, Sonja I and Bernstein, Leslie and Blot, William J and Bottinger, Erwin P and Carpten, John and Chanock, Stephen J and Chen, Yii-Der Ida and Conti, David V and Cooper, Richard S and Fornage, Myriam and Freedman, Barry I and Garcia, Melissa and Goodman, Phyllis J and Hsu, Yu-Han H and Hu, Jennifer and Huff, Chad D and Ingles, Sue A and John, Esther M and Kittles, Rick and Klein, Eric and Li, Jin and McKnight, Barbara and Nayak, Uma and Nemesure, Barbara and Ogunniyi, Adesola and Olshan, Andrew and Press, Michael F and Rohde, Rebecca and Rybicki, Benjamin A and Salako, Babatunde and Sanderson, Maureen and Shao, Yaming and Siscovick, David S and Stanford, Janet L and Stevens, Victoria L and Stram, Alex and Strom, Sara S and Vaidya, Dhananjay and Witte, John S and Yao, Jie and Zhu, Xiaofeng and Ziegler, Regina G and Zonderman, Alan B and Adeyemo, Adebowale and Ambs, Stefan and Cushman, Mary and Faul, Jessica D and Hakonarson, Hakon and Levin, Albert M and Nathanson, Katherine L and Ware, Erin B and Weir, David R and Zhao, Wei and Zhi, Degui and Arnett, Donna K and Grant, Struan F A and Kardia, Sharon L R and Oloapde, Olufunmilayo I and Rao, D C and Rotimi, Charles N and Sale, Mich{\`e}le M and Williams, L Keoki and Zemel, Babette S and Becker, Diane M and Borecki, Ingrid B and Evans, Michele K and Harris, Tamara B and Hirschhorn, Joel N and Li, Yun and Patel, Sanjay R and Psaty, Bruce M and Rotter, Jerome I and Wilson, James G and Bowden, Donald W and Cupples, L Adrienne and Haiman, Christopher A and Loos, Ruth J F and North, Kari E} } @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 {8198, title = {Associations of autozygosity with a broad range of human phenotypes.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 Oct 31}, pages = {4957}, abstract = {

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55\% decrease [95\% CI 44-66\%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.

}, issn = {2041-1723}, doi = {10.1038/s41467-019-12283-6}, author = {Clark, David W and Okada, Yukinori and Moore, Kristjan H S and Mason, Dan and Pirastu, Nicola and Gandin, Ilaria and Mattsson, Hannele and Barnes, Catriona L K and Lin, Kuang and Zhao, Jing Hua and Deelen, Patrick and Rohde, Rebecca and Schurmann, Claudia and Guo, Xiuqing and Giulianini, Franco and Zhang, Weihua and Medina-G{\'o}mez, Carolina and Karlsson, Robert and Bao, Yanchun and Bartz, Traci M and Baumbach, Clemens and Biino, Ginevra and Bixley, Matthew J and Brumat, Marco and Chai, Jin-Fang and Corre, Tanguy and Cousminer, Diana L and Dekker, Annelot M and Eccles, David A and van Eijk, Kristel R and Fuchsberger, Christian and Gao, He and Germain, Marine and Gordon, Scott D and de Haan, Hugoline G and Harris, Sarah E and Hofer, Edith and Huerta-Chagoya, Alicia and Igartua, Catherine and Jansen, Iris E and Jia, Yucheng and Kacprowski, Tim and Karlsson, Torgny and Kleber, Marcus E and Li, Shengchao Alfred and Li-Gao, Ruifang and Mahajan, Anubha and Matsuda, Koichi and Meidtner, Karina and Meng, Weihua and Montasser, May E and van der Most, Peter J and Munz, Matthias and Nutile, Teresa and Palviainen, Teemu and Prasad, Gauri and Prasad, Rashmi B and Priyanka, Tallapragada Divya Sri and Rizzi, Federica and Salvi, Erika and Sapkota, Bishwa R and Shriner, Daniel and Skotte, Line and Smart, Melissa C and Smith, Albert Vernon and van der Spek, Ashley and Spracklen, Cassandra N and Strawbridge, Rona J and Tajuddin, Salman M and Trompet, Stella and Turman, Constance and Verweij, Niek and Viberti, Clara and Wang, Lihua and Warren, Helen R and Wootton, Robyn E and Yanek, Lisa R and Yao, Jie and Yousri, Noha A and Zhao, Wei and Adeyemo, Adebowale A and Afaq, Saima and Aguilar-Salinas, Carlos Alberto and Akiyama, Masato and Albert, Matthew L and Allison, Matthew A and Alver, Maris and Aung, Tin and Azizi, Fereidoun and Bentley, Amy R and Boeing, Heiner and Boerwinkle, Eric and Borja, Judith B and de Borst, Gert J and Bottinger, Erwin P and Broer, Linda and Campbell, Harry and Chanock, Stephen and Chee, Miao-Li and Chen, Guanjie and Chen, Yii-der I and Chen, Zhengming and Chiu, Yen-Feng and Cocca, Massimiliano and Collins, Francis S and Concas, Maria Pina and Corley, Janie and Cugliari, Giovanni and van Dam, Rob M and Damulina, Anna and Daneshpour, Maryam S and Day, Felix R and Delgado, Graciela E and Dhana, Klodian and Doney, Alexander S F and D{\"o}rr, Marcus and Doumatey, Ayo P and Dzimiri, Nduna and Ebenesersd{\'o}ttir, S Sunna and Elliott, Joshua and Elliott, Paul and Ewert, Ralf and Felix, Janine F and Fischer, Krista and Freedman, Barry I and Girotto, Giorgia and Goel, Anuj and G{\"o}gele, Martin and Goodarzi, Mark O and Graff, Mariaelisa and Granot-Hershkovitz, Einat and Grodstein, Francine and Guarrera, Simonetta and Gudbjartsson, Daniel F and Guity, Kamran and Gunnarsson, Bjarni and Guo, Yu and Hagenaars, Saskia P and Haiman, Christopher A and Halevy, Avner and Harris, Tamara B and Hedayati, Mehdi and van Heel, David A and Hirata, Makoto and H{\"o}fer, Imo and Hsiung, Chao Agnes and Huang, Jinyan and Hung, Yi-Jen and Ikram, M Arfan and Jagadeesan, Anuradha and Jousilahti, Pekka and Kamatani, Yoichiro and Kanai, Masahiro and Kerrison, Nicola D and Kessler, Thorsten and Khaw, Kay-Tee and Khor, Chiea Chuen and de Kleijn, Dominique P V and Koh, Woon-Puay and Kolcic, Ivana and Kraft, Peter and Kr{\"a}mer, Bernhard K and Kutalik, Zolt{\'a}n and Kuusisto, Johanna and Langenberg, Claudia and Launer, Lenore J and Lawlor, Deborah A and Lee, I-Te and Lee, Wen-Jane and Lerch, Markus M and Li, Liming and Liu, Jianjun and Loh, Marie and London, Stephanie J and Loomis, Stephanie and Lu, Yingchang and Luan, Jian{\textquoteright}an and M{\"a}gi, Reedik and Manichaikul, Ani W and Manunta, Paolo and M{\'a}sson, G{\'\i}sli and Matoba, Nana and Mei, Xue W and Meisinger, Christa and Meitinger, Thomas and Mezzavilla, Massimo and Milani, Lili and Millwood, Iona Y and Momozawa, Yukihide and Moore, Amy and Morange, Pierre-Emmanuel and Moreno-Macias, Hortensia and Mori, Trevor A and Morrison, Alanna C and Muka, Taulant and Murakami, Yoshinori and Murray, Alison D and de Mutsert, Ren{\'e}e and Mychaleckyj, Josyf C and Nalls, Mike A and Nauck, Matthias and Neville, Matt J and Nolte, Ilja M and Ong, Ken K and Orozco, Lorena and Padmanabhan, Sandosh and P{\'a}lsson, Gunnar and Pankow, James S and Pattaro, Cristian and Pattie, Alison and Polasek, Ozren and Poulter, Neil and Pramstaller, Peter P and Quintana-Murci, Lluis and R{\"a}ikk{\"o}nen, Katri and Ralhan, Sarju and Rao, Dabeeru C and van Rheenen, Wouter and Rich, Stephen S and Ridker, Paul M and Rietveld, Cornelius A and Robino, Antonietta and van Rooij, Frank J A and Ruggiero, Daniela and Saba, Yasaman and Sabanayagam, Charumathi and Sabater-Lleal, Maria and Sala, Cinzia Felicita and Salomaa, Veikko and Sandow, Kevin and Schmidt, Helena and Scott, Laura J and Scott, William R and Sedaghati-Khayat, Bahareh and Sennblad, Bengt and van Setten, Jessica and Sever, Peter J and Sheu, Wayne H-H and Shi, Yuan and Shrestha, Smeeta and Shukla, Sharvari Rahul and Sigurdsson, Jon K and Sikka, Timo Tonis and Singh, Jai Rup and Smith, Blair H and Stan{\v c}{\'a}kov{\'a}, Alena and Stanton, Alice and Starr, John M and Stefansdottir, Lilja and Straker, Leon and Sulem, Patrick and Sveinbjornsson, Gardar and Swertz, Morris A and Taylor, Adele M and Taylor, Kent D and Terzikhan, Natalie and Tham, Yih-Chung and Thorleifsson, Gudmar and Thorsteinsdottir, Unnur and Tillander, Annika and Tracy, Russell P and Tusi{\'e}-Luna, Teresa and Tzoulaki, Ioanna and Vaccargiu, Simona and Vangipurapu, Jagadish and Veldink, Jan H and Vitart, Veronique and V{\"o}lker, Uwe and Vuoksimaa, Eero and Wakil, Salma M and Waldenberger, Melanie and Wander, Gurpreet S and Wang, Ya Xing and Wareham, Nicholas J and Wild, Sarah and Yajnik, Chittaranjan S and Yuan, Jian-Min and Zeng, Lingyao and Zhang, Liang and Zhou, Jie and Amin, Najaf and Asselbergs, Folkert W and Bakker, Stephan J L and Becker, Diane M and Lehne, Benjamin and Bennett, David A and van den Berg, Leonard H and Berndt, Sonja I and Bharadwaj, Dwaipayan and Bielak, Lawrence F and Bochud, Murielle and Boehnke, Mike and Bouchard, Claude and Bradfield, Jonathan P and Brody, Jennifer A and Campbell, Archie and Carmi, Shai and Caulfield, Mark J and Cesarini, David and Chambers, John C and Chandak, Giriraj Ratan and Cheng, Ching-Yu and Ciullo, Marina and Cornelis, Marilyn and Cusi, Daniele and Smith, George Davey and Deary, Ian J and Dorajoo, Rajkumar and van Duijn, Cornelia M and Ellinghaus, David and Erdmann, Jeanette and Eriksson, Johan G and Evangelou, Evangelos and Evans, Michele K and Faul, Jessica D and Feenstra, Bjarke and Feitosa, Mary and Foisy, Sylvain and Franke, Andre and Friedlander, Yechiel and Gasparini, Paolo and Gieger, Christian and Gonzalez, Clicerio and Goyette, Philippe and Grant, Struan F A and Griffiths, Lyn R and Groop, Leif and Gudnason, Vilmundur and Gyllensten, Ulf and Hakonarson, Hakon and Hamsten, Anders and van der Harst, Pim and Heng, Chew-Kiat and Hicks, Andrew A and Hochner, Hagit and Huikuri, Heikki and Hunt, Steven C and Jaddoe, Vincent W V and De Jager, Philip L and Johannesson, Magnus and Johansson, Asa and Jonas, Jost B and Jukema, J Wouter and Junttila, Juhani and Kaprio, Jaakko and Kardia, Sharon L R and Karpe, Fredrik and Kumari, Meena and Laakso, Markku and van der Laan, Sander W and Lahti, Jari and Laudes, Matthias and Lea, Rodney A and Lieb, Wolfgang and Lumley, Thomas and Martin, Nicholas G and M{\"a}rz, Winfried and Matullo, Giuseppe and McCarthy, Mark I and Medland, Sarah E and Merriman, Tony R and Metspalu, Andres and Meyer, Brian F and Mohlke, Karen L and Montgomery, Grant W and Mook-Kanamori, Dennis and Munroe, Patricia B and North, Kari E and Nyholt, Dale R and O{\textquoteright}Connell, Jeffery R and Ober, Carole and Oldehinkel, Albertine J and Palmas, Walter and Palmer, Colin and Pasterkamp, Gerard G and Patin, Etienne and Pennell, Craig E and Perusse, Louis and Peyser, Patricia A and Pirastu, Mario and Polderman, Tinca J C and Porteous, David J and Posthuma, Danielle and Psaty, Bruce M and Rioux, John D and Rivadeneira, Fernando and Rotimi, Charles and Rotter, Jerome I and Rudan, Igor and den Ruijter, Hester M and Sanghera, Dharambir K and Sattar, Naveed and Schmidt, Reinhold and Schulze, Matthias B and Schunkert, Heribert and Scott, Robert A and Shuldiner, Alan R and Sim, Xueling and Small, Neil and Smith, Jennifer A and Sotoodehnia, Nona and Tai, E-Shyong and Teumer, Alexander and Timpson, Nicholas J and Toniolo, Daniela and Tr{\'e}gou{\"e}t, David-Alexandre and Tuomi, Tiinamaija and Vollenweider, Peter and Wang, Carol A and Weir, David R and Whitfield, John B and Wijmenga, Cisca and Wong, Tien-Yin and Wright, John and Yang, Jingyun and Yu, Lei and Zemel, Babette S and Zonderman, Alan B and Perola, Markus and Magnusson, Patrik K E and Uitterlinden, Andr{\'e} G and Kooner, Jaspal S and Chasman, Daniel I and Loos, Ruth J F and Franceschini, Nora and Franke, Lude and Haley, Chris S and Hayward, Caroline and Walters, Robin G and Perry, John R B and Esko, T{\~o}nu and Helgason, Agnar and Stefansson, Kari and Joshi, Peter K and Kubo, Michiaki and Wilson, James F} } @article {8005, title = {Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 Apr}, pages = {636-648}, abstract = {

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

}, issn = {1546-1718}, doi = {10.1038/s41588-019-0378-y}, author = {Bentley, Amy R and Sung, Yun J and Brown, Michael R and Winkler, Thomas W and Kraja, Aldi T and Ntalla, Ioanna and Schwander, Karen and Chasman, Daniel I and Lim, Elise and Deng, Xuan and Guo, Xiuqing and Liu, Jingmin and Lu, Yingchang and Cheng, Ching-Yu and Sim, Xueling and Vojinovic, Dina and Huffman, Jennifer E and Musani, Solomon K and Li, Changwei and Feitosa, Mary F and Richard, Melissa A and Noordam, Raymond and Baker, Jenna and Chen, Guanjie and Aschard, Hugues and Bartz, Traci M and Ding, Jingzhong and Dorajoo, Rajkumar and Manning, Alisa K and Rankinen, Tuomo and Smith, Albert V and Tajuddin, Salman M and Zhao, Wei and Graff, Mariaelisa and Alver, Maris and Boissel, Mathilde and Chai, Jin Fang and Chen, Xu and Divers, Jasmin and Evangelou, Evangelos and Gao, Chuan and Goel, Anuj and Hagemeijer, Yanick and Harris, Sarah E and Hartwig, Fernando P and He, Meian and Horimoto, Andrea R V R and Hsu, Fang-Chi and Hung, Yi-Jen and Jackson, Anne U and Kasturiratne, Anuradhani and Komulainen, Pirjo and Kuhnel, Brigitte and Leander, Karin and Lin, Keng-Hung and Luan, Jian{\textquoteright}an and Lyytik{\"a}inen, Leo-Pekka and Matoba, Nana and Nolte, Ilja M and Pietzner, Maik and Prins, Bram and Riaz, Muhammad and Robino, Antonietta and Said, M Abdullah and Schupf, Nicole and Scott, Robert A and Sofer, Tamar and Stan{\v c}{\'a}kov{\'a}, Alena and Takeuchi, Fumihiko and Tayo, Bamidele O and van der Most, Peter J and Varga, Tibor V and Wang, Tzung-Dau and Wang, Yajuan and Ware, Erin B and Wen, Wanqing and Xiang, Yong-Bing and Yanek, Lisa R and Zhang, Weihua and Zhao, Jing Hua and Adeyemo, Adebowale and Afaq, Saima and Amin, Najaf and Amini, Marzyeh and Arking, Dan E and Arzumanyan, Zorayr and Aung, Tin and Ballantyne, Christie and Barr, R Graham and Bielak, Lawrence F and Boerwinkle, Eric and Bottinger, Erwin P and Broeckel, Ulrich and Brown, Morris and Cade, Brian E and Campbell, Archie and Canouil, Micka{\"e}l and Charumathi, Sabanayagam and Chen, Yii-Der Ida and Christensen, Kaare and Concas, Maria Pina and Connell, John M and de Las Fuentes, Lisa and de Silva, H Janaka and de Vries, Paul S and Doumatey, Ayo and Duan, Qing and Eaton, Charles B and Eppinga, Ruben N and Faul, Jessica D and Floyd, James S and Forouhi, Nita G and Forrester, Terrence and Friedlander, Yechiel and Gandin, Ilaria and Gao, He and Ghanbari, Mohsen and Gharib, Sina A and Gigante, Bruna and Giulianini, Franco and Grabe, Hans J and Gu, C Charles and Harris, Tamara B and Heikkinen, Sami and Heng, Chew-Kiat and Hirata, Makoto and Hixson, James E and Ikram, M Arfan and Jia, Yucheng and Joehanes, Roby and Johnson, Craig and Jonas, Jost Bruno and Justice, Anne E and Katsuya, Tomohiro and Khor, Chiea Chuen and Kilpel{\"a}inen, Tuomas O and Koh, Woon-Puay and Kolcic, Ivana and Kooperberg, Charles and Krieger, Jose E and Kritchevsky, Stephen B and Kubo, Michiaki and Kuusisto, Johanna and Lakka, Timo A and Langefeld, Carl D and Langenberg, Claudia and Launer, Lenore J and Lehne, Benjamin and Lewis, Cora E and Li, Yize and Liang, Jingjing and Lin, Shiow and Liu, Ching-Ti and Liu, Jianjun and Liu, Kiang and Loh, Marie and Lohman, Kurt K and Louie, Tin and Luzzi, Anna and M{\"a}gi, Reedik and Mahajan, Anubha and Manichaikul, Ani W and McKenzie, Colin A and Meitinger, Thomas and Metspalu, Andres and Milaneschi, Yuri and Milani, Lili and Mohlke, Karen L and Momozawa, Yukihide and Morris, Andrew P and Murray, Alison D and Nalls, Mike A and Nauck, Matthias and Nelson, Christopher P and North, Kari E and O{\textquoteright}Connell, Jeffrey R and Palmer, Nicholette D and Papanicolau, George J and Pedersen, Nancy L and Peters, Annette and Peyser, Patricia A and Polasek, Ozren and Poulter, Neil and Raitakari, Olli T and Reiner, Alex P and Renstrom, Frida and Rice, Treva K and Rich, Stephen S and Robinson, Jennifer G and Rose, Lynda M and Rosendaal, Frits R and Rudan, Igor and Schmidt, Carsten O and Schreiner, Pamela J and Scott, William R and Sever, Peter and Shi, Yuan and Sidney, Stephen and Sims, Mario and Smith, Jennifer A and Snieder, Harold and Starr, John M and Strauch, Konstantin and Stringham, Heather M and Tan, Nicholas Y Q and Tang, Hua and Taylor, Kent D and Teo, Yik Ying and Tham, Yih Chung and Tiemeier, Henning and Turner, Stephen T and Uitterlinden, Andr{\'e} G and van Heemst, Diana and Waldenberger, Melanie and Wang, Heming and Wang, Lan and Wang, Lihua and Wei, Wen Bin and Williams, Christine A and Wilson, Gregory and Wojczynski, Mary K and Yao, Jie and Young, Kristin and Yu, Caizheng and Yuan, Jian-Min and Zhou, Jie and Zonderman, Alan B and Becker, Diane M and Boehnke, Michael and Bowden, Donald W and Chambers, John C and Cooper, Richard S and de Faire, Ulf and Deary, Ian J and Elliott, Paul and Esko, T{\~o}nu and Farrall, Martin and Franks, Paul W and Freedman, Barry I and Froguel, Philippe and Gasparini, Paolo and Gieger, Christian and Horta, Bernardo L and Juang, Jyh-Ming Jimmy and Kamatani, Yoichiro and Kammerer, Candace M and Kato, Norihiro and Kooner, Jaspal S and Laakso, Markku and Laurie, Cathy C and Lee, I-Te and Lehtim{\"a}ki, Terho and Magnusson, Patrik K E and Oldehinkel, Albertine J and Penninx, Brenda W J H and Pereira, Alexandre C and Rauramaa, Rainer and Redline, Susan and Samani, Nilesh J and Scott, James and Shu, Xiao-Ou and van der Harst, Pim and Wagenknecht, Lynne E and Wang, Jun-Sing and Wang, Ya Xing and Wareham, Nicholas J and Watkins, Hugh and Weir, David R and Wickremasinghe, Ananda R and Wu, Tangchun and Zeggini, Eleftheria and Zheng, Wei and Bouchard, Claude and Evans, Michele K and Gudnason, Vilmundur and Kardia, Sharon L R and Liu, Yongmei and Psaty, Bruce M and Ridker, Paul M and van Dam, Rob M and Mook-Kanamori, Dennis O and Fornage, Myriam and Province, Michael A and Kelly, Tanika N and Fox, Ervin R and Hayward, Caroline and van Duijn, Cornelia M and Tai, E Shyong and Wong, Tien Yin and Loos, Ruth J F and Franceschini, Nora and Rotter, Jerome I and Zhu, Xiaofeng and Bierut, Laura J and Gauderman, W James and Rice, Kenneth and Munroe, Patricia B and Morrison, Alanna C and Rao, Dabeeru C and Rotimi, Charles N and Cupples, L Adrienne} } @article {8705, title = {Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 Apr 01}, pages = {564-582}, abstract = {

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5\%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained <=20 variants in the credible sets that jointly account for 99\% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.02.011}, author = {Graff, Mariaelisa and Justice, Anne E and Young, Kristin L and Marouli, Eirini and Zhang, Xinruo and Fine, Rebecca S and Lim, Elise and Buchanan, Victoria and Rand, Kristin and Feitosa, Mary F and Wojczynski, Mary K and Yanek, Lisa R and Shao, Yaming and Rohde, Rebecca and Adeyemo, Adebowale A and Aldrich, Melinda C and Allison, Matthew A and Ambrosone, Christine B and Ambs, Stefan and Amos, Christopher and Arnett, Donna K and Atwood, Larry and Bandera, Elisa V and Bartz, Traci and Becker, Diane M and Berndt, Sonja I and Bernstein, Leslie and Bielak, Lawrence F and Blot, William J and Bottinger, Erwin P and Bowden, Donald W and Bradfield, Jonathan P and Brody, Jennifer A and Broeckel, Ulrich and Burke, Gregory and Cade, Brian E and Cai, Qiuyin and Caporaso, Neil and Carlson, Chris and Carpten, John and Casey, Graham and Chanock, Stephen J and Chen, Guanjie and Chen, Minhui and Chen, Yii-der I and Chen, Wei-Min and Chesi, Alessandra and Chiang, Charleston W K and Chu, Lisa and Coetzee, Gerry A and Conti, David V and Cooper, Richard S and Cushman, Mary and Demerath, Ellen and Deming, Sandra L and Dimitrov, Latchezar and Ding, Jingzhong and Diver, W Ryan and Duan, Qing and Evans, Michele K and Falusi, Adeyinka G and Faul, Jessica D and Fornage, Myriam and Fox, Caroline and Freedman, Barry I and Garcia, Melissa and Gillanders, Elizabeth M and Goodman, Phyllis and Gottesman, Omri and Grant, Struan F A and Guo, Xiuqing and Hakonarson, Hakon and Haritunians, Talin and Harris, Tamara B and Harris, Curtis C and Henderson, Brian E and Hennis, Anselm and Hernandez, Dena G and Hirschhorn, Joel N and McNeill, Lorna Haughton and Howard, Timothy D and Howard, Barbara and Hsing, Ann W and Hsu, Yu-Han H and Hu, Jennifer J and Huff, Chad D and Huo, Dezheng and Ingles, Sue A and Irvin, Marguerite R and John, Esther M and Johnson, Karen C and Jordan, Joanne M and Kabagambe, Edmond K and Kang, Sun J and Kardia, Sharon L and Keating, Brendan J and Kittles, Rick A and Klein, Eric A and Kolb, Suzanne and Kolonel, Laurence N and Kooperberg, Charles and Kuller, Lewis and Kutlar, Abdullah and Lange, Leslie and Langefeld, Carl D and Le Marchand, Lo{\"\i}c and Leonard, Hampton and Lettre, Guillaume and Levin, Albert M and Li, Yun and Li, Jin and Liu, Yongmei and Liu, Youfang and Liu, Simin and Lohman, Kurt and Lotay, Vaneet and Lu, Yingchang and Maixner, William and Manson, JoAnn E and McKnight, Barbara and Meng, Yan and Monda, Keri L and Monroe, Kris and Moore, Jason H and Mosley, Thomas H and Mudgal, Poorva and Murphy, Adam B and Nadukuru, Rajiv and Nalls, Mike A and Nathanson, Katherine L and Nayak, Uma and N{\textquoteright}diaye, Amidou and Nemesure, Barbara and Neslund-Dudas, Christine and Neuhouser, Marian L and Nyante, Sarah and Ochs-Balcom, Heather and Ogundiran, Temidayo O and Ogunniyi, Adesola and Ojengbede, Oladosu and Okut, Hayrettin and Olopade, Olufunmilayo I and Olshan, Andrew and Padhukasahasram, Badri and Palmer, Julie and Palmer, Cameron D and Palmer, Nicholette D and Papanicolaou, George and Patel, Sanjay R and Pettaway, Curtis A and Peyser, Patricia A and Press, Michael F and Rao, D C and Rasmussen-Torvik, Laura J and Redline, Susan and Reiner, Alex P and Rhie, Suhn K and Rodriguez-Gil, Jorge L and Rotimi, Charles N and Rotter, Jerome I and Ruiz-Narvaez, Edward A and Rybicki, Benjamin A and Salako, Babatunde and Sale, Mich{\`e}le M and Sanderson, Maureen and Schadt, Eric and Schreiner, Pamela J and Schurmann, Claudia and Schwartz, Ann G and Shriner, Daniel A and Signorello, Lisa B and Singleton, Andrew B and Siscovick, David S and Smith, Jennifer A and Smith, Shad and Speliotes, Elizabeth and Spitz, Margaret and Stanford, Janet L and Stevens, Victoria L and Stram, Alex and Strom, Sara S and Sucheston, Lara and Sun, Yan V and Tajuddin, Salman M and Taylor, Herman and Taylor, Kira and Tayo, Bamidele O and Thun, Michael J and Tucker, Margaret A and Vaidya, Dhananjay and Van Den Berg, David J and Vedantam, Sailaja and Vitolins, Mara and Wang, Zhaoming and Ware, Erin B and Wassertheil-Smoller, Sylvia and Weir, David R and Wiencke, John K and Williams, Scott M and Williams, L Keoki and Wilson, James G and Witte, John S and Wrensch, Margaret and Wu, Xifeng and Yao, Jie and Zakai, Neil and Zanetti, Krista and Zemel, Babette S and Zhao, Wei and Zhao, Jing Hua and Zheng, Wei and Zhi, Degui and Zhou, Jie and Zhu, Xiaofeng and Ziegler, Regina G and Zmuda, Joe and Zonderman, Alan B and Psaty, Bruce M and Borecki, Ingrid B and Cupples, L Adrienne and Liu, Ching-Ti and Haiman, Christopher A and Loos, Ruth and Ng, Maggie C Y and North, Kari E} } @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 {9385, title = {Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.}, journal = {medRxiv}, year = {2023}, month = {2023 Mar 31}, abstract = {

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

}, doi = {10.1101/2023.03.31.23287839}, author = {Suzuki, Ken and Hatzikotoulas, Konstantinos and Southam, Lorraine and Taylor, Henry J and Yin, Xianyong and Lorenz, Kim M and Mandla, Ravi and Huerta-Chagoya, Alicia and Rayner, Nigel W and Bocher, Ozvan and Ana Luiza de, S V Arruda and Sonehara, Kyuto and Namba, Shinichi and Lee, Simon S K and Preuss, Michael H and Petty, Lauren E and Schroeder, Philip and Vanderwerff, Brett and Kals, Mart and Bragg, Fiona and Lin, Kuang and Guo, Xiuqing and Zhang, Weihua and Yao, Jie and Kim, Young Jin and Graff, Mariaelisa and Takeuchi, Fumihiko and Nano, Jana and Lamri, Amel and Nakatochi, Masahiro and Moon, Sanghoon and Scott, Robert A and Cook, James P and Lee, Jung-Jin and Pan, Ian and Taliun, Daniel and Parra, Esteban J and Chai, Jin-Fang and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Thorleifsson, Gudmar and Grarup, Niels and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Kwak, Soo-Heon and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Nongmaithem, Suraj S 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 Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Brody, Jennifer A and Kabagambe, Edmond and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Alaine Broadaway, K and Williamson, Alice and Kamali, Zoha and Cui, Jinrui and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Ahluwalia, Tarunveer S and Anand, Sonia S and Bertoni, Alain and Bork-Jensen, Jette and Brandslund, Ivan and Buchanan, Thomas A and Burant, Charles F and Butterworth, Adam S 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 Danesh, John and Das, Swapan K and Janaka de Silva, H 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 Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Gordon-Larsen, Penny and Gross, Myron and Guare, Lindsay A and Hackinger, Sophie and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Horikoshi, Momoko 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, Torben 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 Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Kyung Min and Lee, Myung-Shik and Lee, Nanette R and Leong, Aaron and Li, Liming and Li, Yun and Li-Gao, Ruifang and Lithgart, 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 Lynch, Julie A and Lyssenko, Valeriya and Maeda, Shiro and Mamakou, Vasiliki and Mansuri, Sohail Rafik and Matsuda, Koichi and Meitinger, Thomas and Metspalu, Andres and Mo, Huan and Morris, Andrew D and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Patil, Snehal and Pei, Pei and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Polikowsky, Hannah G and Porneala, Bianca and Prasad, Gauri and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Katheryn and Sabanayagam, Charumathi and Sandow, Kevin and Sankareswaran, Alagu and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Shahriar, Mohammad and Shen, Botong and Shi, Jinxiu and Shin, Dong Mun and Shojima, Nobuhiro and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Steinthorsdottir, Valgerdur and Stilp, Adrienne M and Strauch, Konstantin and Taylor, Kent D and Thorand, Barbara and Thorsteinsdottir, Unnur and Tomlinson, Brian and Tran, Tam C 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 Wacher-Rodarte, Niels and Wheeler, Eleanor and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamamoto, Kenichi and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zawistowski, Matthew and Zhang, Liang and Zheng, Wei and Project, Biobank Japan and BioBank, Penn Medicine and Center, Regeneron Genetics and Consortium, eMERGE 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 Fornage, Myriam and Hanis, Craig L 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 Yokota, Mitsuhiro and Kardia, Sharon L R and Peyser, Patricia A and Pankow, James S and Engert, James C and Bonnefond, Am{\'e}lie and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Wu, Jer-Yuarn and Geoffrey Hayes, M and Ma, Ronald C W and Wong, Tien-Yin and Mook-Kanamori, Dennis O and Tuomi, Tiinamaija 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 Chen, Yii-Der Ida and Rich, Stephen S and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Ghanbari, Mohsen 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 Bowden, Donald W and Palmer, Colin N A and Kooner, Jaspal S and Kooperberg, Charles and Liu, Simin and North, Kari E and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and Wareham, Nicholas J and Lee, Juyoung and Kim, Bong-Jo and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Goodarzi, Mark O and Mohlke, Karen L and Langenberg, Claudia and Haiman, Christopher A and Loos, Ruth J F and Florez, Jose C and Rader, Daniel J and Ritchie, Marylyn D and Z{\"o}llner, Sebastian and M{\"a}gi, Reedik and Denny, Joshua C and Yamauchi, Toshimasa and Kadowaki, Takashi and Chambers, John C and Ng, Maggie C Y and Sim, Xueling and Below, Jennifer E and Tsao, Philip S and Chang, Kyong-Mi and McCarthy, Mark I and Meigs, James B and Mahajan, Anubha and Spracklen, Cassandra N and Mercader, Josep M and Boehnke, Michael and Rotter, Jerome I and Vujkovic, Marijana and Voight, Benjamin F and Morris, Andrew P and Zeggini, Eleftheria} } @article {9619, title = {Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.}, journal = {Nature}, year = {2024}, month = {2024 Feb 19}, abstract = {

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

}, issn = {1476-4687}, doi = {10.1038/s41586-024-07019-6}, author = {Suzuki, Ken and Hatzikotoulas, Konstantinos and Southam, Lorraine and Taylor, Henry J and Yin, Xianyong and Lorenz, Kim M and Mandla, Ravi and Huerta-Chagoya, Alicia and Melloni, Giorgio E M and Kanoni, Stavroula and Rayner, Nigel W and Bocher, Ozvan and Arruda, Ana Luiza and Sonehara, Kyuto and Namba, Shinichi and Lee, Simon S K and Preuss, Michael H and Petty, Lauren E and Schroeder, Philip and Vanderwerff, Brett and Kals, Mart and Bragg, Fiona and Lin, Kuang and Guo, Xiuqing and Zhang, Weihua and Yao, Jie and Kim, Young Jin and Graff, Mariaelisa and Takeuchi, Fumihiko and Nano, Jana and Lamri, Amel and Nakatochi, Masahiro and Moon, Sanghoon and Scott, Robert A and Cook, James P and Lee, Jung-Jin and Pan, Ian and Taliun, Daniel and Parra, Esteban J and Chai, Jin-Fang and Bielak, Lawrence F and Tabara, Yasuharu and Hai, Yang and Thorleifsson, Gudmar and Grarup, Niels and Sofer, Tamar and Wuttke, Matthias and Sarnowski, Chloe and Gieger, Christian and Nousome, Darryl and Trompet, Stella and Kwak, Soo-Heon and Long, Jirong and Sun, Meng and Tong, Lin and Chen, Wei-Min and Nongmaithem, Suraj S 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 Prins, Bram Peter and Nicolas, Aude and Yanek, Lisa R and Chen, Guanjie and Brody, Jennifer A and Kabagambe, Edmond and An, Ping and Xiang, Anny H and Choi, Hyeok Sun and Cade, Brian E and Tan, Jingyi and Broadaway, K Alaine and Williamson, Alice and Kamali, Zoha and Cui, Jinrui and Thangam, Manonanthini and Adair, Linda S and Adeyemo, Adebowale and Aguilar-Salinas, Carlos A and Ahluwalia, Tarunveer S and Anand, Sonia S and Bertoni, Alain and Bork-Jensen, Jette and Brandslund, Ivan and Buchanan, Thomas A and Burant, Charles F and Butterworth, Adam S 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 Danesh, John 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 Franco, Oscar H and Frayling, Timothy M and Freedman, Barry I and Genter, Pauline and Gerstein, Hertzel C and Giedraitis, Vilmantas and Gonz{\'a}lez-Villalpando, Clicerio and Gonzalez-Villalpando, Maria Elena and Gordon-Larsen, Penny and Gross, Myron and Guare, Lindsay A and Hackinger, Sophie and Hakaste, Liisa and Han, Sohee and Hattersley, Andrew T and Herder, Christian and Horikoshi, Momoko 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, Torben and Kamanu, Frederick K 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 Kronenberg, Florian and Kuusisto, Johanna and L{\"a}ll, Kristi and Lange, Leslie A and Lee, Kyung Min 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 Lynch, Julie A and Lyssenko, Valeriya and Maeda, Shiro and Mamakou, Vasiliki and Mansuri, Sohail Rafik and Matsuda, Koichi and Meitinger, Thomas and Melander, Olle and Metspalu, Andres and Mo, Huan and Morris, Andrew D and Moura, Filipe A and Nadler, Jerry L and Nalls, Michael A and Nayak, Uma and Ntalla, Ioanna and Okada, Yukinori and Orozco, Lorena and Patel, Sanjay R and Patil, Snehal and Pei, Pei and Pereira, Mark A and Peters, Annette and Pirie, Fraser J and Polikowsky, Hannah G and Porneala, Bianca and Prasad, Gauri and Rasmussen-Torvik, Laura J and Reiner, Alexander P and Roden, Michael and Rohde, Rebecca and Roll, Katheryn and Sabanayagam, Charumathi and Sandow, Kevin and Sankareswaran, Alagu and Sattar, Naveed and Sch{\"o}nherr, Sebastian and Shahriar, Mohammad and Shen, Botong and Shi, Jinxiu and Shin, Dong Mun and Shojima, Nobuhiro and Smith, Jennifer A and So, Wing Yee and Stan{\v c}{\'a}kov{\'a}, Alena and Steinthorsdottir, Valgerdur and Stilp, Adrienne M and Strauch, Konstantin and Taylor, Kent D and Thorand, Barbara and Thorsteinsdottir, Unnur and Tomlinson, Brian and Tran, Tam C 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 Wacher-Rodarte, Niels and Wheeler, Eleanor and Wickremasinghe, Ananda R and van Dijk, Ko Willems and Witte, Daniel R and Yajnik, Chittaranjan S and Yamamoto, Ken and Yamamoto, Kenichi and Yoon, Kyungheon and Yu, Canqing and Yuan, Jian-Min and Yusuf, Salim and Zawistowski, Matthew 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 Fornage, Myriam and Hanis, Craig L 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 Yokota, Mitsuhiro and Kardia, Sharon L R and Peyser, Patricia A and Pankow, James S and Engert, James C and Bonnefond, Am{\'e}lie and Froguel, Philippe and Wilson, James G and Sheu, Wayne H H and Wu, Jer-Yuarn and Hayes, M Geoffrey and Ma, Ronald C W and Wong, Tien-Yin and Mook-Kanamori, Dennis O and Tuomi, Tiinamaija 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 Chen, Yii-Der Ida and Rich, Stephen S and McKean-Cowdin, Roberta and Grallert, Harald and Cheng, Ching-Yu and Ghanbari, Mohsen 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 Bowden, Donald W and Palmer, Colin N A and Kooner, Jaspal S and Kooperberg, Charles and Liu, Simin and North, Kari E and Saleheen, Danish and Hansen, Torben and Pedersen, Oluf and Wareham, Nicholas J and Lee, Juyoung and Kim, Bong-Jo and Millwood, Iona Y and Walters, Robin G and Stefansson, Kari and Ahlqvist, Emma and Goodarzi, Mark O and Mohlke, Karen L and Langenberg, Claudia and Haiman, Christopher A and Loos, Ruth J F and Florez, Jose C and Rader, Daniel J and Ritchie, Marylyn D and Z{\"o}llner, Sebastian and M{\"a}gi, Reedik and Marston, Nicholas A and Ruff, Christian T and van Heel, David A and Finer, Sarah and Denny, Joshua C and Yamauchi, Toshimasa and Kadowaki, Takashi and Chambers, John C and Ng, Maggie C Y and Sim, Xueling and Below, Jennifer E and Tsao, Philip S and Chang, Kyong-Mi and McCarthy, Mark I and Meigs, James B and Mahajan, Anubha and Spracklen, Cassandra N and Mercader, Josep M and Boehnke, Michael and Rotter, Jerome I and Vujkovic, Marijana and Voight, Benjamin F and Morris, Andrew P and Zeggini, Eleftheria} }