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2. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Author

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

Published
2024
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3. The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits

Author

Costanzo, Maria C, von Grotthuss, Marcin, Massung, Jeffrey, Jang, Dongkeun, Caulkins, Lizz, Koesterer, Ryan, Gilbert, Clint, Welch, Ryan P, Kudtarkar, Parul, Hoang, Quy, Boughton, Andrew P, Singh, Preeti, Sun, Ying, Duby, Marc, Moriondo, Annie, Nguyen, Trang, Smadbeck, Patrick, Alexander, Benjamin R, Brandes, MacKenzie, Carmichael, Mary, Dornbos, Peter, Green, Todd, Huellas-Bruskiewicz, Kenneth C, Ji, Yue, Kluge, Alexandria, McMahon, Aoife C, Mercader, Josep M, Ruebenacker, Oliver, Sengupta, Sebanti, Spalding, Dylan, Taliun, Daniel, Consortium, AMP-T2D, Abecasis, Gonçalo, Akolkar, Beena, Allred, Nicholette D, Altshuler, David, Below, Jennifer E, Bergman, Richard, Beulens, Joline WJ, Blangero, John, Boehnke, Michael, Bokvist, Krister, Bottinger, Erwin, Bowden, Donald, Brosnan, M Julia, Brown, Christopher, Bruskiewicz, Kenneth, Burtt, Noël P, Cebola, Inês, Chambers, John, Chen, Yii-Der Ida, Cherkas, Andriy, Chu, Audrey Y, Clark, Christopher, Claussnitzer, Melina, Cox, Nancy J, Hoed, Marcel den, Dong, Duc, Duggirala, Ravindranath, Dupuis, Josée, Elders, Petra JM, Engreitz, Jesse M, Fauman, Eric, Ferrer, Jorge, Flannick, Jason, Flicek, Paul, Flickinger, Matthew, Florez, Jose C, Fox, Caroline S, Frayling, Timothy M, Frazer, Kelly A, Gaulton, Kyle J, Gloyn, Anna L, Hanis, Craig L, Hanson, Robert, Hattersley, Andrew T, Im, Hae Kyung, Iqbal, Sidra, Jacobs, Suzanne BR, Jang, Dong-Keun, Jordan, Tad, Kamphaus, Tania, Karpe, Fredrik, Keane, Thomas M, Kim, Seung K, Lage, Kasper, Lange, Leslie A, and Lazar, Mitchell

Subjects
Genetics, Diabetes, Human Genome, Metabolic and endocrine, Good Health and Well Being, Humans, Diabetes Mellitus, Type 2, Access to Information, Prospective Studies, Genomics, Phenotype, AMP-T2D Consortium, CMDKP, GWAS, T2DKP, data sharing, diabetes, effector genes, genetic associations, genetic support, genomics, portal, Biochemistry and Cell Biology, Medical Biochemistry and Metabolomics, Endocrinology & Metabolism
Abstract

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

Published
2023

4. Leveraging pleiotropy to discover and interpret GWAS results for sleep-associated traits

Author

Chun, Sung, Akle, Sebastian, Teodosiadis, Athanasios, Cade, Brian E, Wang, Heming, Sofer, Tamar, Evans, Daniel S, Stone, Katie L, Gharib, Sina A, Mukherjee, Sutapa, Palmer, Lyle J, Hillman, David, Rotter, Jerome I, Hanis, Craig L, Stamatoyannopoulos, John A, Redline, Susan, Cotsapas, Chris, and Sunyaev, Shamil R

Subjects
Biological Sciences, Genetics, Lung, Prevention, Human Genome, Sleep Research, Aetiology, 2.1 Biological and endogenous factors, Humans, Genome-Wide Association Study, Phenotype, Genetic Association Studies, Sleep Apnea, Obstructive, Sleep, Genetic Pleiotropy, Polymorphism, Single Nucleotide, DNA Primase, Developmental Biology
Abstract

Genetic association studies of many heritable traits resulting from physiological testing often have modest sample sizes due to the cost and burden of the required phenotyping. This reduces statistical power and limits discovery of multiple genetic associations. We present a strategy to leverage pleiotropy between traits to both discover new loci and to provide mechanistic hypotheses of the underlying pathophysiology. Specifically, we combine a colocalization test with a locus-level test of pleiotropy. In simulations, we show that this approach is highly selective for identifying true pleiotropy driven by the same causative variant, thereby improves the chance to replicate the associations in underpowered validation cohorts and leads to higher interpretability. Here, as an exemplar, we use Obstructive Sleep Apnea (OSA), a common disorder diagnosed using overnight multi-channel physiological testing. We leverage pleiotropy with relevant cellular and cardio-metabolic phenotypes and gene expression traits to map new risk loci in an underpowered OSA GWAS. We identify several pleiotropic loci harboring suggestive associations to OSA and genome-wide significant associations to other traits, and show that their OSA association replicates in independent cohorts of diverse ancestries. By investigating pleiotropic loci, our strategy allows proposing new hypotheses about OSA pathobiology across many physiological layers. For example, we identify and replicate the pleiotropy across the plateletcrit, OSA and an eQTL of DNA primase subunit 1 (PRIM1) in immune cells. We find suggestive links between OSA, a measure of lung function (FEV1/FVC), and an eQTL of matrix metallopeptidase 15 (MMP15) in lung tissue. We also link a previously known genome-wide significant peak for OSA in the hexokinase 1 (HK1) locus to hematocrit and other red blood cell related traits. Thus, the analysis of pleiotropic associations has the potential to assemble diverse phenotypes into a chain of mechanistic hypotheses that provide insight into the pathogenesis of complex human diseases.

Published
2022

6. Whole-genome association analyses of sleep-disordered breathing phenotypes in the NHLBI TOPMed program

Author

Cade, Brian E, Lee, Jiwon, Sofer, Tamar, Wang, Heming, Zhang, Man, Chen, Han, Gharib, Sina A, Gottlieb, Daniel J, Guo, Xiuqing, Lane, Jacqueline M, Liang, Jingjing, Lin, Xihong, Mei, Hao, Patel, Sanjay R, Purcell, Shaun M, Saxena, Richa, Shah, Neomi A, Evans, Daniel S, Hanis, Craig L, Hillman, David R, Mukherjee, Sutapa, Palmer, Lyle J, Stone, Katie L, Tranah, Gregory J, Abecasis, Gonçalo R, Boerwinkle, Eric A, Correa, Adolfo, Cupples, L Adrienne, Kaplan, Robert C, Nickerson, Deborah A, North, Kari E, Psaty, Bruce M, Rotter, Jerome I, Rich, Stephen S, Tracy, Russell P, Vasan, Ramachandran S, Wilson, James G, Zhu, Xiaofeng, and Redline, Susan

Subjects
Biological Sciences, Genetics, Sleep Research, Dental/Oral and Craniofacial Disease, Lung, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Alleles, Chromatin Immunoprecipitation Sequencing, Female, Gene Expression Regulation, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Precision Medicine, Research, Signal Transduction, Sleep Apnea Syndromes, United States, Whole Genome Sequencing, Sleep-disordered breathing, Sleep apnea, Whole-genome sequencing, WGS, Genome-wide association study, GWAS, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Sleep Working Group, Clinical Sciences
Abstract

BackgroundSleep-disordered breathing is a common disorder associated with significant morbidity. The genetic architecture of sleep-disordered breathing remains poorly understood. Through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program, we performed the first whole-genome sequence analysis of sleep-disordered breathing.MethodsThe study sample was comprised of 7988 individuals of diverse ancestry. Common-variant and pathway analyses included an additional 13,257 individuals. We examined five complementary traits describing different aspects of sleep-disordered breathing: the apnea-hypopnea index, average oxyhemoglobin desaturation per event, average and minimum oxyhemoglobin saturation across the sleep episode, and the percentage of sleep with oxyhemoglobin saturation

Published
2021

8. Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Author

Goodrich, Julia K, Singer-Berk, Moriel, Son, Rachel, Sveden, Abigail, Wood, Jordan, England, Eleina, Cole, Joanne B, Weisburd, Ben, Watts, Nick, Caulkins, Lizz, Dornbos, Peter, Koesterer, Ryan, Zappala, Zachary, Zhang, Haichen, Maloney, Kristin A, Dahl, Andy, Aguilar-Salinas, Carlos A, Atzmon, Gil, Barajas-Olmos, Francisco, Barzilai, Nir, Blangero, John, Boerwinkle, Eric, Bonnycastle, Lori L, Bottinger, Erwin, Bowden, Donald W, Centeno-Cruz, Federico, Chambers, John C, Chami, Nathalie, Chan, Edmund, Chan, Juliana, Cheng, Ching-Yu, Cho, Yoon Shin, Contreras-Cubas, Cecilia, Córdova, Emilio, Correa, Adolfo, DeFronzo, Ralph A, Duggirala, Ravindranath, Dupuis, Josée, Garay-Sevilla, Ma Eugenia, García-Ortiz, Humberto, Gieger, Christian, Glaser, Benjamin, González-Villalpando, Clicerio, Gonzalez, Ma Elena, Grarup, Niels, Groop, Leif, Gross, Myron, Haiman, Christopher, Han, Sohee, Hanis, Craig L, Hansen, Torben, Heard-Costa, Nancy L, Henderson, Brian E, Hernandez, Juan Manuel Malacara, Hwang, Mi Yeong, Islas-Andrade, Sergio, Jørgensen, Marit E, Kang, Hyun Min, Kim, Bong-Jo, Kim, Young Jin, Koistinen, Heikki A, Kooner, Jaspal Singh, Kuusisto, Johanna, Kwak, Soo-Heon, Laakso, Markku, Lange, Leslie, Lee, Jong-Young, Lee, Juyoung, Lehman, Donna M, Linneberg, Allan, Liu, Jianjun, Loos, Ruth JF, Lyssenko, Valeriya, Ma, Ronald CW, Martínez-Hernández, Angélica, Meigs, James B, Meitinger, Thomas, Mendoza-Caamal, Elvia, Mohlke, Karen L, Morris, Andrew D, Morrison, Alanna C, Ng, Maggie CY, Nilsson, Peter M, O'Donnell, Christopher J, Orozco, Lorena, Palmer, Colin NA, Park, Kyong Soo, Post, Wendy S, Pedersen, Oluf, Preuss, Michael, Psaty, Bruce M, Reiner, Alexander P, Revilla-Monsalve, Cristina, Rich, Stephen S, Rotter, Jerome I, Saleheen, Danish, Schurmann, Claudia, Sim, Xueling, Sladek, Rob, and Small, Kerrin S

Subjects
AMP-T2D-GENES Consortia, Humans, Diabetes Mellitus, Type 2, Genetic Predisposition to Disease, Risk Assessment, Genotype, Multifactorial Inheritance, Penetrance, Adult, Dyslipidemias, Exome, Biomarkers, Biological Variation, Population
Abstract

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

Published
2021

9. Evidence for gene-smoking interactions for hearing loss and deafness in Japanese American families

Author

Wan, Jia Y, Cataby, Christina, Liem, Andrew, Jeffrey, Emily, Norden-Krichmar, Trina M, Goodman, Deborah, Santorico, Stephanie A, Edwards, Karen L, Group, American Diabetes Association GENNID Study, Boerwinkle, Eric, Buse, John, DeFronzo, Ralph, Ehrmann, David, Elbein, Steven C, Fujimoto, Wilfred, Kahn, Steven E, Hanis, Craig L, Mulivor, Richard A, Beck, Jeanne C, Norris, Jill, Permutt, M Alan, Behn, Philip, Raffel, Leslie, and Robbins, David C

Subjects
Clinical Research, Human Genome, Diabetes, Tobacco Smoke and Health, Genetics, Tobacco, Prevention, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Cancer, Adaptor Proteins, Signal Transducing, Adult, Aged, Asian, Cyclic Nucleotide Phosphodiesterases, Type 7, Deafness, Female, Gene-Environment Interaction, Genetic Predisposition to Disease, Genome-Wide Association Study, Hearing, Humans, Japan, Male, Membrane Proteins, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Prevalence, Repressor Proteins, Risk Assessment, Risk Factors, Smoking, United States, Gene-environment interaction, Genome-wide linkage, Hearing loss, Family, Linkage, American Diabetes Association GENNID Study Group, Clinical Sciences, Neurosciences, Medical Physiology, Otorhinolaryngology
Abstract

BackgroundThis study investigated the relationship between smoking and hearing loss and deafness (HLD) and whether the relationship is modified by genetic variation. Data for these analyses was from the subset of Japanese American families collected as part of the American Diabetes Association Genetics of Non-insulin Dependent Diabetes Mellitus study. Logistic regression with generalized estimating equations assessed the relationship between HLD and smoking. Nonparametric linkage analysis identified genetic regions harboring HLD susceptibility genes and ordered subset analysis was used to identify regions showing evidence for gene-smoking interactions. Genetic variants within these candidate regions were then each tested for interaction with smoking using logistic regression models.ResultsAfter adjusting for age, sex, diabetes status and smoking duration, for each pack of cigarettes smoked per day, risk of HLD increased 4.58 times (odds ratio (OR) = 4.58; 95% Confidence Interval (CI): (1.40,15.03)), and ever smokers were over 5 times more likely than nonsmokers to report HLD (OR = 5.22; 95% CI: (1.24, 22.03)). Suggestive evidence for linkage for HLD was observed in multiple genomic regions (Chromosomes 5p15, 8p23 and 17q21), and additional suggestive regions were identified when considering interactions with smoking status (Chromosomes 7p21, 11q23, 12q32, 15q26, and 20q13) and packs-per-day (Chromosome 8q21).ConclusionsTo our knowledge this was the first report of possible gene-by-smoking interactions in HLD using family data. Additional work, including independent replication, is needed to understand the basis of these findings. HLD are important public health issues and understanding the contributions of genetic and environmental factors may inform public health messages and policies.

Published
2020

10. The Type 2 Diabetes Knowledge Portal: An open access genetic resource dedicated to type 2 diabetes and related traits

Author

Abecasis, Gonçalo, Akolkar, Beena, Alexander, Benjamin R., Allred, Nicholette D., Altshuler, David, Below, Jennifer E., Bergman, Richard, Beulens, Joline W.J., Blangero, John, Boehnke, Michael, Bokvist, Krister, Bottinger, Erwin, Boughton, Andrew P., Bowden, Donald, Brosnan, M. Julia, Brown, Christopher, Bruskiewicz, Kenneth, Burtt, Noël P., Carmichael, Mary, Caulkins, Lizz, Cebola, Inês, Chambers, John, Ida Chen, Yii-Der, Cherkas, Andriy, Chu, Audrey Y., Clark, Christopher, Claussnitzer, Melina, Costanzo, Maria C., Cox, Nancy J., Hoed, Marcel den, Dong, Duc, Duby, Marc, Duggirala, Ravindranath, Dupuis, Josée, Elders, Petra J.M., Engreitz, Jesse M., Fauman, Eric, Ferrer, Jorge, Flannick, Jason, Flicek, Paul, Flickinger, Matthew, Florez, Jose C., Fox, Caroline S., Frayling, Timothy M., Frazer, Kelly A., Gaulton, Kyle J., Gilbert, Clint, Gloyn, Anna L., Green, Todd, Hanis, Craig L., Hanson, Robert, Hattersley, Andrew T., Hoang, Quy, Im, Hae Kyung, Iqbal, Sidra, Jacobs, Suzanne B.R., Jang, Dong-Keun, Jordan, Tad, Kamphaus, Tania, Karpe, Fredrik, Keane, Thomas M., Kim, Seung K., Kluge, Alexandria, Koesterer, Ryan, Kudtarkar, Parul, Lage, Kasper, Lange, Leslie A., Lazar, Mitchell, Lehman, Donna, Liu, Ching-Ti, Loos, Ruth J.F., Ma, Ronald Ching-wan, MacDonald, Patrick, Massung, Jeffrey, Maurano, Matthew T., McCarthy, Mark I., McVean, Gil, Meigs, James B., Mercader, Josep M., Miller, Melissa R., Mitchell, Braxton, Mohlke, Karen L., Morabito, Samuel, Morgan, Claire, Mullican, Shannon, Narendra, Sharvari, Ng, Maggie C.Y., Nguyen, Lynette, Palmer, Colin N.A., Parker, Stephen C.J., Parrado, Antonio, Parsa, Afshin, Pawlyk, Aaron C., Pearson, Ewan R., Plump, Andrew, Province, Michael, Quertermous, Thomas, Redline, Susan, Reilly, Dermot F., Ren, Bing, Rich, Stephen S., Richards, J. Brent, Rotter, Jerome I., Ruebenacker, Oliver, Ruetten, Hartmut, Salem, Rany M., Sander, Maike, Sanders, Michael, Sanghera, Dharambir, Scott, Laura J., Sengupta, Sebanti, Siedzik, David, Sim, Xueling, Singh, Preeti, Sladek, Robert, Small, Kerrin, Smith, Philip, Stein, Peter, Spalding, Dylan, Stringham, Heather M., Sun, Ying, Susztak, Katalin, ’t Hart, Leen M., Taliun, Daniel, Taylor, Kent, Thomas, Melissa K., Todd, Jennifer A., Udler, Miriam S., Voight, Benjamin, von Grotthuss, Marcin, Wan, Andre, Welch, Ryan P., Wholley, David, Yuksel, Kaan, Zaghloul, Norann A., Jang, Dongkeun, Moriondo, Annie, Nguyen, Trang, Smadbeck, Patrick, Brandes, MacKenzie, Dornbos, Peter, Huellas-Bruskiewicz, Kenneth C., Ji, Yue, McMahon, Aoife C., Fauman, Eric B., Kamphaus, Tania Nayak, and Abecasis, Gonçalo R.

Published
2023
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11. Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author

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

Published
2022
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12. A Genome-Wide Association Study Identifies Blood Disorder–Related Variants Influencing Hemoglobin A1c With Implications for Glycemic Status in U.S. Hispanics/Latinos

Author

Moon, Jee-Young, Louie, Tin L, Jain, Deepti, Sofer, Tamar, Schurmann, Claudia, Below, Jennifer E, Lai, Chao-Qiang, Aviles-Santa, M Larissa, Talavera, Gregory A, Smith, Caren E, Petty, Lauren E, Bottinger, Erwin P, Chen, Yii-Der Ida, Taylor, Kent D, Daviglus, Martha L, Cai, Jianwen, Wang, Tao, Tucker, Katherine L, Ordovás, José M, Hanis, Craig L, Loos, Ruth JF, Schneiderman, Neil, Rotter, Jerome I, Kaplan, Robert C, and Qi, Qibin

Subjects
Biomedical and Clinical Sciences, Health Sciences, Genetics, Diabetes, Rare Diseases, Hematology, Prevention, 2.1 Biological and endogenous factors, Aetiology, Adult, Alleles, Blood Glucose, Diabetes Mellitus, Fasting, Female, Genetic Variation, Genome-Wide Association Study, Glucose Tolerance Test, Glycated Hemoglobin, Hematologic Diseases, Hispanic or Latino, Humans, Hyperglycemia, Male, Middle Aged, Phenotype, Prediabetic State, Prevalence, United States, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences
Abstract

ObjectiveWe aimed to identify hemoglobin A1c (HbA1c)-associated genetic variants and examine their implications for glycemic status evaluated by HbA1c in U.S. Hispanics/Latinos with diverse genetic ancestries.Research design and methodsWe conducted a genome-wide association study (GWAS) of HbA1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies.ResultsOur GWAS and replication analyses showed 10 previously known and novel loci associated with HbA1c at genome-wide significance levels (P < 5.0 × 10-8). In particular, two African ancestry-specific variants, HBB-rs334 and G6PD-rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA1c levels (β = -0.31% [-3.4 mmol/mol]) and -0.35% [-3.8 mmol/mol] per minor allele, respectively) compared with other HbA1c-associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM-rs145546625, was associated with HbA1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB-rs334 or G6PD-rs1050828 HbA1c-lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA1c level taking HBB-rs334 and G6PD-rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28).ConclusionsThis study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA1c test is performed.

Published
2019

13. Admixture mapping identifies novel loci for obstructive sleep apnea in Hispanic/Latino Americans

Author

Wang, Heming, Cade, Brian E, Sofer, Tamar, Sands, Scott A, Chen, Han, Browning, Sharon R, Stilp, Adrienne M, Louie, Tin L, Thornton, Timothy A, Johnson, W Craig, Below, Jennifer E, Conomos, Matthew P, Evans, Daniel S, Gharib, Sina A, Guo, Xiuqing, Wood, Alexis C, Mei, Hao, Yaffe, Kristine, Loredo, Jose S, Ramos, Alberto R, Barrett-Connor, Elizabeth, Ancoli-Israel, Sonia, Zee, Phyllis C, Arens, Raanan, Shah, Neomi A, Taylor, Kent D, Tranah, Gregory J, Stone, Katie L, Hanis, Craig L, Wilson, James G, Gottlieb, Daniel J, Patel, Sanjay R, Rice, Ken, Post, Wendy S, Rotter, Jerome I, Sunyaev, Shamil R, Cai, Jianwen, Lin, Xihong, Purcell, Shaun M, Laurie, Cathy C, Saxena, Richa, Redline, Susan, and Zhu, Xiaofeng

Subjects
Biological Sciences, Genetics, Sleep Research, Lung, Aged, Chromosome Mapping, Female, Ferrochelatase, Genome-Wide Association Study, Genotype, Hispanic or Latino, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Polysomnography, Sleep Apnea, Obstructive, White People, Medical and Health Sciences, Genetics & Heredity
Abstract

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Its prevalence and severity vary across ancestral background. Although OSA traits are heritable, few genetic associations have been identified. To identify genetic regions associated with OSA and improve statistical power, we applied admixture mapping on three primary OSA traits [the apnea hypopnea index (AHI), overnight average oxyhemoglobin saturation (SaO2) and percentage time SaO2

Published
2019

14. Multiethnic Genome-wide Association Study of Diabetic Retinopathy using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

Author

Pollack, Samuela, Igo, Robert P, Jensen, Richard A, Christiansen, Mark, Li, Xiaohui, Cheng, Ching-Yu, Ng, Maggie CY, Smith, Albert V, Rossin, Elizabeth J, Segrè, Ayellet V, Davoudi, Samaneh, Tan, Gavin S, Chen, Yii-Der Ida, Kuo, Jane Z, Dimitrov, Latchezar M, Stanwyck, Lynn K, Meng, Weihua, Hosseini, S Mohsen, Imamura, Minako, Nousome, Darryl, Kim, Jihye, Hai, Yang, Jia, Yucheng, Ahn, Jeeyun, Leong, Aaron, Shah, Kaanan, Park, Kyu Hyung, Guo, Xiuqing, Ipp, Eli, Taylor, Kent D, Adler, Sharon G, Sedor, John R, Freedman, Barry I, Group, DCCT EDIC Research Group Family Investigation of Nephropathy and Diabetes-Eye Research, Lee, I-Te, Sheu, Wayne H-H, Kubo, Michiaki, Takahashi, Atsushi, Hadjadj, Samy, Marre, Michel, Tregouet, David-Alexandre, Mckean-Cowdin, Roberta, Varma, Rohit, McCarthy, Mark I, Groop, Leif, Ahlqvist, Emma, Lyssenko, Valeriya, Agardh, Elisabet, Morris, Andrew, Doney, Alex SF, Colhoun, Helen M, Toppila, Iiro, Sandholm, Niina, Groop, Per-Henrik, Maeda, Shiro, Hanis, Craig L, Penman, Alan, Chen, Ching J, Hancock, Heather, Mitchell, Paul, Craig, Jamie E, Chew, Emily Y, Paterson, Andrew D, Grassi, Michael A, Palmer, Colin, Bowden, Donald W, Yaspan, Brian L, Siscovick, David, Cotch, Mary Frances, Wang, Jie Jin, Burdon, Kathryn P, Wong, Tien Y, Klein, Barbara EK, Klein, Ronald, Rotter, Jerome I, Iyengar, Sudha K, Price, Alkes, and Sobrin, Lucia

Subjects
Biomedical and Clinical Sciences, Genetics, Eye Disease and Disorders of Vision, Diabetes, Human Genome, Prevention, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Good Health and Well Being, Blood Glucose, Diabetes Mellitus, Type 2, Diabetic Retinopathy, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Glycated Hemoglobin, Humans, Meta-Analysis as Topic, Polymorphism, Single Nucleotide, Protein Binding, Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value

Published
2019

15. GWAS of QRS duration identifies new loci specific to Hispanic/Latino populations

Author

Swenson, Brenton R, Louie, Tin, Lin, Henry J, Méndez-Giráldez, Raúl, Below, Jennifer E, Laurie, Cathy C, Kerr, Kathleen F, Highland, Heather, Thornton, Timothy A, Ryckman, Kelli K, Kooperberg, Charles, Soliman, Elsayed Z, Seyerle, Amanda A, Guo, Xiuqing, Taylor, Kent D, Yao, Jie, Heckbert, Susan R, Darbar, Dawood, Petty, Lauren E, McKnight, Barbara, Cheng, Susan, Bello, Natalie A, Whitsel, Eric A, Hanis, Craig L, Nalls, Mike A, Evans, Daniel S, Rotter, Jerome I, Sofer, Tamar, Avery, Christy L, and Sotoodehnia, Nona

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Cardiovascular, Human Genome, Heart Disease, Good Health and Well Being, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Hispanic or Latino, Humans, Middle Aged, Molecular Sequence Annotation, Phenotype, Polymorphism, Single Nucleotide, General Science & Technology
Abstract

BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.MethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.ResultsWe identified six loci associated with QRS (P

Published
2019

16. Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep

Author

Cade, Brian E, Chen, Han, Stilp, Adrienne M, Louie, Tin, Ancoli-Israel, Sonia, Arens, Raanan, Barfield, Richard, Below, Jennifer E, Cai, Jianwen, Conomos, Matthew P, Evans, Daniel S, Frazier-Wood, Alexis C, Gharib, Sina A, Gleason, Kevin J, Gottlieb, Daniel J, Hillman, David R, Johnson, W Craig, Lederer, David J, Lee, Jiwon, Loredo, Jose S, Mei, Hao, Mukherjee, Sutapa, Patel, Sanjay R, Post, Wendy S, Purcell, Shaun M, Ramos, Alberto R, Reid, Kathryn J, Rice, Ken, Shah, Neomi A, Sofer, Tamar, Taylor, Kent D, Thornton, Timothy A, Wang, Heming, Yaffe, Kristine, Zee, Phyllis C, Hanis, Craig L, Palmer, Lyle J, Rotter, Jerome I, Stone, Katie L, Tranah, Gregory J, Wilson, James G, Sunyaev, Shamil R, Laurie, Cathy C, Zhu, Xiaofeng, Saxena, Richa, Lin, Xihong, and Redline, Susan

Subjects
Genetics, Lung, Sleep Research, Clinical Research, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Adult, Aged, Aged, 80 and over, Cell Adhesion Molecules, Neuronal, Computational Biology, Extracellular Matrix Proteins, Female, Gene Regulatory Networks, Genetic Variation, Genome-Wide Association Study, Hexokinase, Humans, Hypoxia, Interleukin-18 Receptor alpha Subunit, Male, Middle Aged, NLR Family, Pyrin Domain-Containing 3 Protein, Nerve Tissue Proteins, Oxygen, Oxyhemoglobins, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reelin Protein, Serine Endopeptidases, Sleep, Sleep Apnea Syndromes, Young Adult, Developmental Biology
Abstract

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10(-6) were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10(-10)). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10(-8)). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

Published
2019

17. Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea–related Quantitative Trait Locus in Men

Author

Chen, Han, Cade, Brian E, Gleason, Kevin J, Bjonnes, Andrew C, Stilp, Adrienne M, Sofer, Tamar, Conomos, Matthew P, Ancoli-Israel, Sonia, Arens, Raanan, Azarbarzin, Ali, Bell, Graeme I, Below, Jennifer E, Chun, Sung, Evans, Daniel S, Ewert, Ralf, Frazier-Wood, Alexis C, Gharib, Sina A, Haba-Rubio, José, Hagen, Erika W, Heinzer, Raphael, Hillman, David R, Johnson, W Craig, Kutalik, Zoltan, Lane, Jacqueline M, Larkin, Emma K, Lee, Seung Ku, Liang, Jingjing, Loredo, Jose S, Mukherjee, Sutapa, Palmer, Lyle J, Papanicolaou, George J, Penzel, Thomas, Peppard, Paul E, Post, Wendy S, Ramos, Alberto R, Rice, Ken, Rotter, Jerome I, Sands, Scott A, Shah, Neomi A, Shin, Chol, Stone, Katie L, Stubbe, Beate, Sul, Jae Hoon, Tafti, Mehdi, Taylor, Kent D, Teumer, Alexander, Thornton, Timothy A, Tranah, Gregory J, Wang, Chaolong, Wang, Heming, Warby, Simon C, Wellman, D Andrew, Zee, Phyllis C, Hanis, Craig L, Laurie, Cathy C, Gottlieb, Daniel J, Patel, Sanjay R, Zhu, Xiaofeng, Sunyaev, Shamil R, Saxena, Richa, Lin, Xihong, and Redline, Susan

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Genetics, Sleep Research, Clinical Research, Human Genome, Lung, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Phosphatidylethanolamine N-Methyltransferase, Quantitative Trait Loci, Sex Characteristics, Sleep Apnea, Obstructive, Sleep, REM, Sterol Regulatory Element Binding Protein 1, Trans-Activators, Transcription Factors, ras Proteins, obstructive sleep apnea, genetics, genome-wide association studies, multiethnic, sexual dimorphism, Cardiorespiratory Medicine and Haematology, Respiratory System, Biochemistry and cell biology, Cardiovascular medicine and haematology
Abstract

Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10-8) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.

Published
2018

18. Evaluating the contribution of rare variants to type 2 diabetes and related traits using pedigrees

Author

Jun, Goo, Manning, Alisa, Almeida, Marcio, Zawistowski, Matthew, Wood, Andrew R, Teslovich, Tanya M, Fuchsberger, Christian, Feng, Shuang, Cingolani, Pablo, Gaulton, Kyle J, Dyer, Thomas, Blackwell, Thomas W, Chen, Han, Chines, Peter S, Choi, Sungkyoung, Churchhouse, Claire, Fontanillas, Pierre, King, Ryan, Lee, SungYoung, Lincoln, Stephen E, Trubetskoy, Vasily, DePristo, Mark, Fingerlin, Tasha, Grossman, Robert, Grundstad, Jason, Heath, Alison, Kim, Jayoun, Kim, Young Jin, Laramie, Jason, Lee, Jaehoon, Li, Heng, Liu, Xuanyao, Livne, Oren, Locke, Adam E, Maller, Julian, Mazur, Alexander, Morris, Andrew P, Pollin, Toni I, Ragona, Derek, Reich, David, Rivas, Manuel A, Scott, Laura J, Sim, Xueling, Tearle, Rick G, Teo, Yik Ying, Williams, Amy L, Zöllner, Sebastian, Curran, Joanne E, Peralta, Juan, Akolkar, Beena, Bell, Graeme I, Burtt, Noël P, Cox, Nancy J, Florez, Jose C, Hanis, Craig L, McKeon, Catherine, Mohlke, Karen L, Seielstad, Mark, Wilson, James G, Atzmon, Gil, Below, Jennifer E, Dupuis, Josée, Nicolae, Dan L, Lehman, Donna, Park, Taesung, Won, Sungho, Sladek, Robert, Altshuler, David, McCarthy, Mark I, Duggirala, Ravindranath, Boehnke, Michael, Frayling, Timothy M, Abecasis, Gonçalo R, and Blangero, John

Subjects
Diabetes, Genetics, Human Genome, Clinical Research, Obesity, Genetic Testing, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Diabetes Mellitus, Type 2, Family Health, Female, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Mexican Americans, Pedigree, Phenotype, Quantitative Trait Loci, Whole Genome Sequencing, genetics, sequencing, type 2 diabetes, eQTL, rare variants
Abstract

A major challenge in evaluating the contribution of rare variants to complex disease is identifying enough copies of the rare alleles to permit informative statistical analysis. To investigate the contribution of rare variants to the risk of type 2 diabetes (T2D) and related traits, we performed deep whole-genome analysis of 1,034 members of 20 large Mexican-American families with high prevalence of T2D. If rare variants of large effect accounted for much of the diabetes risk in these families, our experiment was powered to detect association. Using gene expression data on 21,677 transcripts for 643 pedigree members, we identified evidence for large-effect rare-variant cis-expression quantitative trait loci that could not be detected in population studies, validating our approach. However, we did not identify any rare variants of large effect associated with T2D, or the related traits of fasting glucose and insulin, suggesting that large-effect rare variants account for only a modest fraction of the genetic risk of these traits in this sample of families. Reliable identification of large-effect rare variants will require larger samples of extended pedigrees or different study designs that further enrich for such variants.

Published
2018

19. Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study

Author

Sobrin, Lucia, Chong, Yong He, Fan, Qiao, Gan, Alfred, Stanwyck, Lynn K, Kaidonis, Georgia, Craig, Jamie E, Kim, Jihye, Liao, Wen-Ling, Huang, Yu-Chuen, Lee, Wen-Jane, Hung, Yi-Jen, Guo, Xiuqing, Hai, Yang, Ipp, Eli, Pollack, Samuela, Hancock, Heather, Price, Alkes, Penman, Alan, Mitchell, Paul, Liew, Gerald, Smith, Albert V, Gudnason, Vilmundur, Tan, Gavin, Klein, Barbara EK, Kuo, Jane, Li, Xiaohui, Christiansen, Mark W, Psaty, Bruce M, Sandow, Kevin, Jensen, Richard A, Klein, Ronald, Cotch, Mary Frances, Wang, Jie Jin, Jia, Yucheng, Chen, Ching J, Chen, Yii-Der Ida, Rotter, Jerome I, Tsai, Fuu-Jen, Hanis, Craig L, Burdon, Kathryn P, Wong, Tien Yin, Cheng, Ching-Yu, Spracklen, Cassandra N, Chen, Peng, Kim, Young Jin, Wang, Xu, Cai, Hui, Li, Shengxu, Long, Jirong, Wu, Ying, Wang, Ya-Xing, Takeuchi, Fumihiko, Wu, Jer-Yuarn, Jung, Keum-Ji, Hu, Cheng, Akiyama, Koichi, Zhang, Yonghong, Moon, Sanghoon, Johnson, Todd A, Li, Huaixing, Dorajoo, Rajkumar, He, Meian, Cannon, Maren E, Roman, Tamara S, Salfati, Elias, Lin, Keng-Hung, Sheu, Wayne HH, Absher, Devin, Adair, Linda S, Assimes, Themistocles L, Aung, Tin, Cai, Qiuyin, Chang, Li-Ching, Chen, Chien-Hsiun, Chien, Li-Hsin, Chuang, Lee-Ming, Chuang, Shu-Chun, Du, Shufa, Fann, Cathy SJ, Feranil, Alan B, Friedlander, Yechiel, Gordon-Larsen, Penny, Gu, Dongfeng, Gui, Lixuan, Guo, Zhirong, Heng, Chew-Kiat, Hixson, James, Hou, Xuhong, Hsiung, Chao Agnes, Hu, Yao, Hwang, Mi Yeong, Hwu, Chii-Min, Isono, Masato, Juang, Jyh-Ming Jimmy, Khor, Chiea-Chuen, Kim, Yun Kyoung, Koh, Woon-Puay, Kubo, Michiaki, and Lee, I-Te

Subjects
Biomedical and Clinical Sciences, Cancer, Prevention, Eye Disease and Disorders of Vision, 2.1 Biological and endogenous factors, Aetiology, Metabolic and endocrine, Aged, Diabetic Retinopathy, Female, Genome-Wide Association Study, Humans, Lipids, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Risk, Asian Genetic Epidemiology Network Consortium, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.

Published
2017

20. Transitioning From an In-Person Intervention to Augmented Text Messaging During COVID-19 in Mexican Americans With Prediabetes: The Starr County Diabetes Prevention Randomized Clinical Trial

Author

Brown, Sharon A., primary, Winter, Mary A., additional, Becker, Heather A., additional, García, Alexandra A., additional, Velasquez, Mary M., additional, Tanaka, Hirofumi, additional, Perkison, William B., additional, Brown, Eric L., additional, Aguilar, David, additional, and Hanis, Craig L., additional

Published
2024
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21. GWAS of the electrocardiographic QT interval in Hispanics/Latinos generalizes previously identified loci and identifies population-specific signals

Author

Méndez-Giráldez, Raúl, Gogarten, Stephanie M, Below, Jennifer E, Yao, Jie, Seyerle, Amanda A, Highland, Heather M, Kooperberg, Charles, Soliman, Elsayed Z, Rotter, Jerome I, Kerr, Kathleen F, Ryckman, Kelli K, Taylor, Kent D, Petty, Lauren E, Shah, Sanjiv J, Conomos, Matthew P, Sotoodehnia, Nona, Cheng, Susan, Heckbert, Susan R, Sofer, Tamar, Guo, Xiuqing, Whitsel, Eric A, Lin, Henry J, Hanis, Craig L, Laurie, Cathy C, and Avery, Christy L

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Heart Disease, Cardiovascular, Electrocardiography, Genetic Loci, Genome-Wide Association Study, Genotype, Hispanic or Latino, Humans, KCNQ1 Potassium Channel, Linkage Disequilibrium, Long QT Syndrome, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide, Sodium-Potassium-Exchanging ATPase
Abstract

QT interval prolongation is a heritable risk factor for ventricular arrhythmias and can predispose to sudden death. Most genome-wide association studies (GWAS) of QT were performed in European ancestral populations, leaving other groups uncharacterized. Herein we present the first QT GWAS of Hispanic/Latinos using data on 15,997 participants from four studies. Study-specific summary results of the association between 1000 Genomes Project (1000G) imputed SNPs and electrocardiographically measured QT were combined using fixed-effects meta-analysis. We identified 41 genome-wide significant SNPs that mapped to 13 previously identified QT loci. Conditional analyses distinguished six secondary signals at NOS1AP (n = 2), ATP1B1 (n = 2), SCN5A (n = 1), and KCNQ1 (n = 1). Comparison of linkage disequilibrium patterns between the 13 lead SNPs and six secondary signals with previously reported index SNPs in 1000G super populations suggested that the SCN5A and KCNE1 lead SNPs were potentially novel and population-specific. Finally, of the 42 suggestively associated loci, AJAP1 was suggestively associated with QT in a prior East Asian GWAS; in contrast BVES and CAP2 murine knockouts caused cardiac conduction defects. Our results indicate that whereas the same loci influence QT across populations, population-specific variation exists, motivating future trans-ethnic and ancestrally diverse QT GWAS.

Published
2017

22. Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level

Author

Wang, Heming, Cade, Brian E, Chen, Han, Gleason, Kevin J, Saxena, Richa, Feng, Tao, Larkin, Emma K, Vasan, Ramachandran S, Lin, Honghuang, Patel, Sanjay R, Tracy, Russell P, Liu, Yongmei, Gottlieb, Daniel J, Below, Jennifer E, Hanis, Craig L, Petty, Lauren E, Sunyaev, Shamil R, Frazier-Wood, Alexis C, Rotter, Jerome I, Post, Wendy, Lin, Xihong, Redline, Susan, and Zhu, Xiaofeng

Subjects
Genetics, Lung, Sleep Research, 2.1 Biological and endogenous factors, Aetiology, Adult, Angiopoietin-2, Female, Genetic Association Studies, Genetic Linkage, Genetic Predisposition to Disease, Haplotypes, Humans, Male, Oxygen, Oxygen Consumption, Oxyhemoglobins, Polymorphism, Single Nucleotide, Respiration, Sleep, Sleep Apnea Syndromes, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Genetic determinants of sleep-disordered breathing (SDB), a common set of disorders that contribute to significant cardiovascular and neuropsychiatric morbidity, are not clear. Overnight nocturnal oxygen saturation (SaO2) is a clinically relevant and easily measured indicator of SDB severity but its genetic contribution has never been studied. Our recent study suggests nocturnal SaO2 is heritable. We performed linkage analysis, association analysis and haplotype analysis of average nocturnal oxyhaemoglobin saturation in participants in the Cleveland Family Study (CFS), followed by gene-based association and additional tests in four independent samples. Linkage analysis identified a peak (LOD = 4.29) on chromosome 8p23. Follow-up association analysis identified two haplotypes in angiopoietin-2 (ANGPT2) that significantly contributed to the variation of SaO2 (P = 8 × 10-5) and accounted for a portion of the linkage evidence. Gene-based association analysis replicated the association of ANGPT2 and nocturnal SaO2. A rare missense SNP rs200291021 in ANGPT2 was associated with serum angiopoietin-2 level (P = 1.29 × 10-4), which was associated with SaO2 (P = 0.002). Our study provides the first evidence for the association of ANGPT2, a gene previously implicated in acute lung injury syndromes, with nocturnal SaO2, suggesting that this gene has a broad range of effects on gas exchange, including influencing oxygenation during sleep.

Published
2016

23. Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans

Author

Cade, Brian E, Chen, Han, Stilp, Adrienne M, Gleason, Kevin J, Sofer, Tamar, Ancoli-Israel, Sonia, Arens, Raanan, Bell, Graeme I, Below, Jennifer E, Bjonnes, Andrew C, Chun, Sung, Conomos, Matthew P, Evans, Daniel S, Johnson, W Craig, Frazier-Wood, Alexis C, Lane, Jacqueline M, Larkin, Emma K, Loredo, Jose S, Post, Wendy S, Ramos, Alberto R, Rice, Ken, Rotter, Jerome I, Shah, Neomi A, Stone, Katie L, Taylor, Kent D, Thornton, Timothy A, Tranah, Gregory J, Wang, Chaolong, Zee, Phyllis C, Hanis, Craig L, Sunyaev, Shamil R, Patel, Sanjay R, Laurie, Cathy C, Zhu, Xiaofeng, Saxena, Richa, Lin, Xihong, and Redline, Susan

Subjects
Genetics, Clinical Research, Lung, Aging, Prevention, Sleep Research, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, sleep apnea, hypoxia, genetics, GWAS, Prader-Willi syndrome, Prader–Willi syndrome, Medical and Health Sciences, Respiratory System
Abstract

RationaleObstructive sleep apnea is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. Although there is strong clinical and epidemiologic evidence supporting the importance of genetic factors in influencing obstructive sleep apnea, its genetic basis is still largely unknown. Prior genetic studies focused on traits defined using the apnea-hypopnea index, which contains limited information on potentially important genetically determined physiologic factors, such as propensity for hypoxemia and respiratory arousability.ObjectivesTo define novel obstructive sleep apnea genetic risk loci for obstructive sleep apnea, we conducted genome-wide association studies of quantitative traits in Hispanic/Latino Americans from three cohorts.MethodsGenome-wide data from as many as 12,558 participants in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Starr County Health Studies population-based cohorts were metaanalyzed for association with the apnea-hypopnea index, average oxygen saturation during sleep, and average respiratory event duration.Measurements and main resultsTwo novel loci were identified at genome-level significance (rs11691765, GPR83, P = 1.90 × 10-8 for the apnea-hypopnea index, and rs35424364; C6ORF183/CCDC162P, P = 4.88 × 10-8 for respiratory event duration) and seven additional loci were identified with suggestive significance (P

Published
2016

24. Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects and tissue-specific enrichment of eQTLs

Author

Below, Jennifer E, Parra, Esteban J, Gamazon, Eric R, Torres, Jason, Krithika, S, Candille, Sophie, Lu, Yingchang, Manichakul, Ani, Peralta-Romero, Jesus, Duan, Qing, Li, Yun, Morris, Andrew P, Gottesman, Omri, Bottinger, Erwin, Wang, Xin-Qun, Taylor, Kent D, Ida Chen, Y-D, Rotter, Jerome I, Rich, Stephen S, Loos, Ruth JF, Tang, Hua, Cox, Nancy J, Cruz, Miguel, Hanis, Craig L, and Valladares-Salgado, Adan

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Atherosclerosis, Genetic Association Studies, Genetics, Population, Genome-Wide Association Study, Genotype, Hispanic or Latino, Humans, Linkage Disequilibrium, Lipid Metabolism, Lipids, Mexico, Organ Specificity, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Quantitative Trait, Heritable, White People
Abstract

We performed genome-wide meta-analysis of lipid traits on three samples of Mexican and Mexican American ancestry comprising 4,383 individuals, and followed up significant and highly suggestive associations in three additional Hispanic samples comprising 7,876 individuals. Genome-wide significant signals were observed in or near CELSR2, ZNF259/APOA5, KANK2/DOCK6 and NCAN/MAU2 for total cholesterol, LPL, ABCA1, ZNF259/APOA5, LIPC and CETP for HDL cholesterol, CELSR2, APOB and NCAN/MAU2 for LDL cholesterol, and GCKR, TRIB1, ZNF259/APOA5 and NCAN/MAU2 for triglycerides. Linkage disequilibrium and conditional analyses indicate that signals observed at ABCA1 and LIPC for HDL cholesterol and NCAN/MAU2 for triglycerides are independent of previously reported lead SNP associations. Analyses of lead SNPs from the European Global Lipids Genetics Consortium (GLGC) dataset in our Hispanic samples show remarkable concordance of direction of effects as well as strong correlation in effect sizes. A meta-analysis of the European GLGC and our Hispanic datasets identified five novel regions reaching genome-wide significance: two for total cholesterol (FN1 and SAMM50), two for HDL cholesterol (LOC100996634 and COPB1) and one for LDL cholesterol (LINC00324/CTC1/PFAS). The top meta-analysis signals were found to be enriched for SNPs associated with gene expression in a tissue-specific fashion, suggesting an enrichment of tissue-specific function in lipid-associated loci.

Published
2016

28. Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium

Author

Palmer, Nicholette D, Goodarzi, Mark O, Langefeld, Carl D, Wang, Nan, Guo, Xiuqing, Taylor, Kent D, Fingerlin, Tasha E, Norris, Jill M, Buchanan, Thomas A, Xiang, Anny H, Haritunians, Talin, Ziegler, Julie T, Williams, Adrienne H, Stefanovski, Darko, Cui, Jinrui, Mackay, Adrienne W, Henkin, Leora F, Bergman, Richard N, Gao, Xiaoyi, Gauderman, James, Varma, Rohit, Hanis, Craig L, Cox, Nancy J, Highland, Heather M, Below, Jennifer E, Williams, Amy L, Burtt, Noel P, Aguilar-Salinas, Carlos A, Huerta-Chagoya, Alicia, Gonzalez-Villalpando, Clicerio, Orozco, Lorena, Haiman, Christopher A, Tsai, Michael Y, Johnson, W Craig, Yao, Jie, Rasmussen-Torvik, Laura, Pankow, James, Snively, Beverly, Jackson, Rebecca D, Liu, Simin, Nadler, Jerry L, Kandeel, Fouad, Chen, Yii-Der I, Bowden, Donald W, Rich, Stephen S, Raffel, Leslie J, Rotter, Jerome I, Watanabe, Richard M, and Wagenknecht, Lynne E

Subjects
Biomedical and Clinical Sciences, Obesity, Clinical Research, Diabetes, Human Genome, Genetics, Metabolic and endocrine, Blood Glucose, Databases, Factual, Diabetes Mellitus, Type 2, Gene Expression Regulation, Genetic Variation, Genome, Genome-Wide Association Study, Genotype, Hispanic or Latino, Homeostasis, Humans, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random-effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 × 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D.

Published
2015

29. Variants for HDL-C, LDL-C, and Triglycerides Identified from Admixture Mapping and Fine-Mapping Analysis in African American Families

Author

Shetty, Priya B, Tang, Hua, Feng, Tao, Tayo, Bamidele, Morrison, Alanna C, Kardia, Sharon LR, Hanis, Craig L, Arnett, Donna K, Hunt, Steven C, Boerwinkle, Eric, Rao, Dabeeru C, Cooper, Richard S, Risch, Neil, and Zhu, Xiaofeng

Subjects
Atherosclerosis, Genetics, Heart Disease, Human Genome, Prevention, Cardiovascular, Aetiology, 2.1 Biological and endogenous factors, Adult, Black or African American, Aged, Aged, 80 and over, Cardiovascular Diseases, Cholesterol, HDL, Cholesterol, LDL, Chromosome Mapping, Chromosomes, Human, Family, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Triglycerides, admixture mapping, African Americans, association studies, genetics, lipids, Candidate Gene Association Resource (CARe) Consortium, Medical Biotechnology, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology
Abstract

BackgroundAdmixture mapping of lipids was followed-up by family-based association analysis to identify variants for cardiovascular disease in African Americans.Methods and resultsThe present study conducted admixture mapping analysis for total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. The analysis was performed in 1905 unrelated African American subjects from the National Heart, Lung and Blood Institute's Family Blood Pressure Program (FBPP). Regions showing admixture evidence were followed-up with family-based association analysis in 3556 African American subjects from the FBPP. The admixture mapping and family-based association analyses were adjusted for age, age(2), sex, body mass index, and genome-wide mean ancestry to minimize the confounding caused by population stratification. Regions that were suggestive of local ancestry association evidence were found on chromosomes 7 (low-density lipoprotein cholesterol), 8 (high-density lipoprotein cholesterol), 14 (triglycerides), and 19 (total cholesterol and triglycerides). In the fine-mapping analysis, 52 939 single-nucleotide polymorphisms (SNPs) were tested and 11 SNPs (8 independent SNPs) showed nominal significant association with high-density lipoprotein cholesterol (2 SNPs), low-density lipoprotein cholesterol (4 SNPs), and triglycerides (5 SNPs). The family data were used in the fine-mapping to identify SNPs that showed novel associations with lipids and regions, including genes with known associations for cardiovascular disease.ConclusionsThis study identified regions on chromosomes 7, 8, 14, and 19 and 11 SNPs from the fine-mapping analysis that were associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides for further studies of cardiovascular disease in African Americans.

Published
2015

30. Identification and functional characterization of G6PC2 coding variants influencing glycemic traits define an effector transcript at the G6PC2-ABCB11 locus.

Author

Mahajan, Anubha, Sim, Xueling, Ng, Hui Jin, Manning, Alisa, Rivas, Manuel A, Highland, Heather M, Locke, Adam E, Grarup, Niels, Im, Hae Kyung, Cingolani, Pablo, Flannick, Jason, Fontanillas, Pierre, Fuchsberger, Christian, Gaulton, Kyle J, Teslovich, Tanya M, Rayner, N William, Robertson, Neil R, Beer, Nicola L, Rundle, Jana K, Bork-Jensen, Jette, Ladenvall, Claes, Blancher, Christine, Buck, David, Buck, Gemma, Burtt, Noël P, Gabriel, Stacey, Gjesing, Anette P, Groves, Christopher J, Hollensted, Mette, Huyghe, Jeroen R, Jackson, Anne U, Jun, Goo, Justesen, Johanne Marie, Mangino, Massimo, Murphy, Jacquelyn, Neville, Matt, Onofrio, Robert, Small, Kerrin S, Stringham, Heather M, Syvänen, Ann-Christine, Trakalo, Joseph, Abecasis, Goncalo, Bell, Graeme I, Blangero, John, Cox, Nancy J, Duggirala, Ravindranath, Hanis, Craig L, Seielstad, Mark, Wilson, James G, Christensen, Cramer, Brandslund, Ivan, Rauramaa, Rainer, Surdulescu, Gabriela L, Doney, Alex SF, Lannfelt, Lars, Linneberg, Allan, Isomaa, Bo, Tuomi, Tiinamaija, Jørgensen, Marit E, Jørgensen, Torben, Kuusisto, Johanna, Uusitupa, Matti, Salomaa, Veikko, Spector, Timothy D, Morris, Andrew D, Palmer, Colin NA, Collins, Francis S, Mohlke, Karen L, Bergman, Richard N, Ingelsson, Erik, Lind, Lars, Tuomilehto, Jaakko, Hansen, Torben, Watanabe, Richard M, Prokopenko, Inga, Dupuis, Josee, Karpe, Fredrik, Groop, Leif, Laakso, Markku, Pedersen, Oluf, Florez, Jose C, Morris, Andrew P, Altshuler, David, Meigs, James B, Boehnke, Michael, McCarthy, Mark I, Lindgren, Cecilia M, Gloyn, Anna L, and T2D-GENES consortium and GoT2D consortium

Subjects
T2D-GENES consortium and GoT2D consortium, Humans, Diabetes Mellitus, Type 2, Insulin, Glucose-6-Phosphatase, Blood Glucose, Receptors, Glucagon, Glycemic Index, Gene Frequency, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Exome, Glucagon-Like Peptide-1 Receptor, Diabetes Mellitus, Type 2, Receptors, Glucagon, Polymorphism, Single Nucleotide, Genetics, Developmental Biology
Abstract

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P

Published
2015

33. Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping

Author

Shetty, Priya B, Tang, Hua, Tayo, Bamidele O, Morrison, Alanna C, Hanis, Craig L, Rao, Dabeeru C, Young, Jeffery H, Fox, Ervin R, Boerwinkle, Eric, Cooper, Richard S, Risch, Neil J, and Zhu, Xiaofeng

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Cardiovascular, Hypertension, Biotechnology, Genetics, Obesity, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Black or African American, Blood Pressure, Chromosomes, Human, Pair 21, Coxsackie and Adenovirus Receptor-Like Membrane Protein, Female, Humans, Male, Polymorphism, Single Nucleotide, Receptors, Thrombin, African-Americans, blood pressure, genetic association studies, obesity, Candidate Gene Association Resource (CARe) Consortium, Cardiorespiratory Medicine and Haematology, Medical Physiology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences
Abstract

ObjectiveGenetic variants in 296 genes in regions identified through admixture mapping of hypertension, BMI, and lipids were assessed for association with hypertension, blood pressure (BP), BMI, and high-density lipoprotein cholesterol (HDL-C).MethodsThis study identified coding SNPs identified from HapMap2 data that were located in genes on chromosomes 5, 6, 8, and 21, wherein ancestry association evidence for hypertension, BMI, or HDL-C was identified in previous admixture mapping studies. Genotyping was performed in 1733 unrelated African-Americans from the National Heart, Lung and Blood Institute's Family Blood Pressure Project, and gene-based association analyses were conducted for hypertension, SBP, DBP, BMI, and HDL-C. A gene score based on the number of minor alleles of each SNP in a gene was created and used for gene-based regression analyses, adjusting for age, age, sex, local marker ancestry, and BMI, as applicable. An individual's African ancestry estimated from 2507 ancestry-informative markers was also adjusted for to eliminate any confounding due to population stratification.ResultsCXADR (rs437470) on chromosome 21 was associated with SBP and DBP with or without adjusting for local ancestry (P

Published
2012

36. Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications

Author

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

Subjects
Article
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

Published
2023

37. Acculturation, Dietary Behaviors, and Macronutrient Intake Among Mexican Americans With Prediabetes: The Starr County Diabetes Prevention Initiative

Author

Brown, Sharon A., primary, Becker, Heather A., additional, García, Alexandra A., additional, Velasquez, Mary M., additional, Tanaka, Hirofumi, additional, Winter, Mary A., additional, Perkison, William B., additional, Brown, Eric L., additional, Aguilar, David, additional, and Hanis, Craig L., additional

Published
2023
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39. The effects of gender and country of origin on acculturation, psychological factors, lifestyle factors, and diabetes-related physiological outcomes among Mexican Americans: The Starr County diabetes prevention initiative.

Author

Brown, Sharon A, Becker, Heather A, García, Alexandra A, Velasquez, Mary M, Tanaka, Hirofumi, Winter, Mary A, Perkison, William B, Brown, Eric L, Aguilar, David, and Hanis, Craig L

Subjects
DIABETES prevention, LIFESTYLES, MEXICAN Americans, RELATIVE medical risk, ANALYSIS of variance, ACCULTURATION, MULTIVARIATE analysis, HISPANIC Americans, POPULATION geography, REGRESSION analysis, SEX distribution, PHYSIOLOGICAL adaptation, SPANISH language, COMPARATIVE studies, PSYCHOSOCIAL factors, MENTAL depression, RESEARCH funding, PSYCHOLOGICAL adaptation, PEOPLE with diabetes, PREDIABETIC state, INSULIN resistance
Abstract

Objectives: Examine acculturation and psychological, lifestyle, and physiological factors based on gender and country of origin (U.S. vs. Mexico). Methods: Baseline data from the Starr County diabetes prevention study (N = 300) were analyzed – acculturation (language), psychological factors (depression), lifestyle factors (sedentary behaviors), and diabetes-related physiological outcomes (insulin resistance). MANOVA and linear regression were used to examine variable relationships based on gender and country of origin and identify predictors of depression and insulin resistance. Results: Participants were: predominantly female (73%); 51 years of age, on average; born in Mexico (71%); and Spanish-speaking. Individuals spent 11 of their waking hours (range = 0–18 h) in sedentary activities. Compared to females, more males spoke English and reported fewer hours in sedentary activities. Compared to participants born in Mexico, those born in the U.S. were more likely to: speak English; report depressive symptoms; and exhibit elevated BMI and insulin resistance rates. Two distinct models significantly predicted depression (R2 = 14.5%) and insulin resistance (R2 = 26.8%), with acculturation-language entering into both models. Discussion: Significant gender and country-of-origin differences were found. Future research on diabetes prevention should examine other Hispanic subgroups and strategies for addressing individual differences, while employing cost-effective group interventions that incorporate these differences and reach more at-risk individuals. [ABSTRACT FROM AUTHOR]

Published
2023
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40. The genetic architecture of type 2 diabetes

Author

Fuchsberger, Christian, Flannick, Jason, Teslovich, Tanya M., Mahajan, Anubha, Agarwala, Vineeta, Gaulton, Kyle J., Ma, Clement, Fontanillas, Pierre, Moutsianas, Loukas, McCarthy, Davis J., Rivas, Manuel A., Perry, John R. B., Sim, Xueling, Blackwell, Thomas W., Robertson, Neil R., Rayner, N. William, Cingolani, Pablo, Locke, Adam E., Tajes, Juan Fernandez, Highland, Heather M., Dupuis, Josee, Chines, Peter S., Lindgren, Cecilia M., Hartl, Christopher, Jackson, Anne U., Chen, Han, Huyghe, Jeroen R., van de Bunt, Martijn, Pearson, Richard D., Kumar, Ashish, Müller-Nurasyid, Martina, Grarup, Niels, Stringham, Heather M., Gamazon, Eric R., Lee, Jaehoon, Chen, Yuhui, Scott, Robert A., Below, Jennifer E., Chen, Peng, Huang, Jinyan, Go, Min Jin, Stitzel, Michael L., Pasko, Dorota, Parker, Stephen C. J., Varga, Tibor V., Green, Todd, Beer, Nicola L., Day-Williams, Aaron G., Ferreira, Teresa, Fingerlin, Tasha, Horikoshi, Momoko, Hu, Cheng, Huh, Iksoo, Ikram, Mohammad Kamran, Kim, Bong-Jo, Kim, Yongkang, Kim, Young Jin, Kwon, Min-Seok, Lee, Juyoung, Lee, Selyeong, Lin, Keng-Han, Maxwell, Taylor J., Nagai, Yoshihiko, Wang, Xu, Welch, Ryan P., Yoon, Joon, Zhang, Weihua, Barzilai, Nir, Voight, Benjamin F., Han, Bok-Ghee, Jenkinson, Christopher P., Kuulasmaa, Teemu, Kuusisto, Johanna, Manning, Alisa, Ng, Maggie C. Y., Palmer, Nicholette D., Balkau, Beverley, Stančáková, Alena, Abboud, Hanna E., Boeing, Heiner, Giedraitis, Vilmantas, Prabhakaran, Dorairaj, Gottesman, Omri, Scott, James, Carey, Jason, Kwan, Phoenix, Grant, George, Smith, Joshua D., Neale, Benjamin M., Purcell, Shaun, Butterworth, Adam S., Howson, Joanna M. M., Lee, Heung Man, Lu, Yingchang, Kwak, Soo-Heon, Zhao, Wei, Danesh, John, Lam, Vincent K. L., Park, Kyong Soo, Saleheen, Danish, So, Wing Yee, Tam, Claudia H. T., Afzal, Uzma, Aguilar, David, Arya, Rector, Aung, Tin, Chan, Edmund, Navarro, Carmen, Cheng, Ching-Yu, Palli, Domenico, Correa, Adolfo, Curran, Joanne E., Rybin, Denis, Farook, Vidya S., Fowler, Sharon P., Freedman, Barry I., Griswold, Michael, Hale, Daniel Esten, Hicks, Pamela J., Khor, Chiea-Chuen, Kumar, Satish, Lehne, Benjamin, Thuillier, Dorothée, Lim, Wei Yen, Liu, Jianjun, van der Schouw, Yvonne T., Loh, Marie, Musani, Solomon K., Puppala, Sobha, Scott, William R., Yengo, Loïc, Tan, Sian-Tsung, Taylor Jr., Herman A., Thameem, Farook, Wilson, Gregory, Wong, Tien Yin, Njølstad, Pål Rasmus, Levy, Jonathan C., Mangino, Massimo, Bonnycastle, Lori L., Schwarzmayr, Thomas, Fadista, João, Surdulescu, Gabriela L., Herder, Christian, Groves, Christopher J., Wieland, Thomas, Bork-Jensen, Jette, Brandslund, Ivan, Christensen, Cramer, Koistinen, Heikki A., Doney, Alex S. F., Kinnunen, Leena, Esko, Tõnu, Farmer, Andrew J., Hakaste, Liisa, Hodgkiss, Dylan, Kravic, Jasmina, Lyssenko, Valeriya, Hollensted, Mette, Jørgensen, Marit E., Jørgensen, Torben, Ladenvall, Claes, Justesen, Johanne Marie, Käräjämäki, Annemari, Kriebel, Jennifer, Rathmann, Wolfgang, Lannfelt, Lars, Lauritzen, Torsten, Narisu, Narisu, Linneberg, Allan, Melander, Olle, Milani, Lili, Neville, Matt, Orho-Melander, Marju, Qi, Lu, Qi, Qibin, Roden, Michael, Rolandsson, Olov, Swift, Amy, Rosengren, Anders H., Stirrups, Kathleen, Wood, Andrew R., Mihailov, Evelin, Blancher, Christine, Carneiro, Mauricio O., Maguire, Jared, Poplin, Ryan, Shakir, Khalid, Fennell, Timothy, DePristo, Mark, Hrabé de Angelis, Martin, Deloukas, Panos, Gjesing, Anette P., Jun, Goo, Nilsson, Peter, Murphy, Jacquelyn, Onofrio, Robert, Thorand, Barbara, Hansen, Torben, Meisinger, Christa, Hu, Frank B., Isomaa, Bo, Karpe, Fredrik, Liang, Liming, Peters, Annette, Huth, Cornelia, O’Rahilly, Stephen P., Palmer, Colin N. A., Pedersen, Oluf, Rauramaa, Rainer, Tuomilehto, Jaakko, Salomaa, Veikko, Watanabe, Richard M., Syvänen, Ann-Christine, Bergman, Richard N., Bharadwaj, Dwaipayan, Bottinger, Erwin P., Cho, Yoon Shin, Chandak, Giriraj R., Chan, Juliana C. N., Chia, Kee Seng, Daly, Mark J., Ebrahim, Shah B., Langenberg, Claudia, Elliott, Paul, Jablonski, Kathleen A., Lehman, Donna M., Jia, Weiping, Ma, Ronald C. W., Pollin, Toni I., Sandhu, Manjinder, Tandon, Nikhil, Froguel, Philippe, Barroso, Inês, Teo, Yik Ying, Zeggini, Eleftheria, Loos, Ruth J. F., Small, Kerrin S., Ried, Janina S., DeFronzo, Ralph A., Grallert, Harald, Glaser, Benjamin, Metspalu, Andres, Wareham, Nicholas J., Walker, Mark, Banks, Eric, Gieger, Christian, Ingelsson, Erik, Im, Hae Kyung, Illig, Thomas, Franks, Paul W., Buck, Gemma, Trakalo, Joseph, Buck, David, Prokopenko, Inga, Mägi, Reedik, Lind, Lars, Farjoun, Yossi, Owen, Katharine R., Gloyn, Anna L., Strauch, Konstantin, Tuomi, Tiinamaija, Kooner, Jaspal Singh, Lee, Jong-Young, Park, Taesung, Donnelly, Peter, Morris, Andrew D., Hattersley, Andrew T., Bowden, Donald W., Collins, Francis S., Atzmon, Gil, Chambers, John C., Spector, Timothy D., Laakso, Markku, Strom, Tim M., Bell, Graeme I., Blangero, John, Duggirala, Ravindranath, Tai, E. Shyong, McVean, Gilean, Hanis, Craig L., Wilson, James G., Seielstad, Mark, Frayling, Timothy M., Meigs, James B., Cox, Nancy J., Sladek, Rob, Lander, Eric S., Gabriel, Stacey, Burtt, Noël P., Mohlke, Karen L., Meitinger, Thomas, Groop, Leif, Abecasis, Goncalo, Florez, Jose C., Scott, Laura J., Morris, Andrew P., Kang, Hyun Min, Boehnke, Michael, Altshuler, David, and McCarthy, Mark I.

Published
2016
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42. The effects of gender and country of origin on acculturation, psychological factors, lifestyle factors, and diabetes-related physiological outcomes among Mexican Americans: The Starr County diabetes prevention initiative

Author

Brown, Sharon A, primary, Becker, Heather A, additional, García, Alexandra A, additional, Velasquez, Mary M, additional, Tanaka, Hirofumi, additional, Winter, Mary A, additional, Perkison, William B, additional, Brown, Eric L, additional, Aguilar, David, additional, and Hanis, Craig L, additional

Published
2022
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46. Rare coding variants in 35 genes associate with circulating lipid levels—A multi-ancestry analysis of 170,000 exomes

Author

Hindy, George, primary, Dornbos, Peter, additional, Chaffin, Mark D., additional, Liu, Dajiang J., additional, Wang, Minxian, additional, Selvaraj, Margaret Sunitha, additional, Zhang, David, additional, Park, Joseph, additional, Aguilar-Salinas, Carlos A., additional, Antonacci-Fulton, Lucinda, additional, Ardissino, Diego, additional, Arnett, Donna K., additional, Aslibekyan, Stella, additional, Atzmon, Gil, additional, Ballantyne, Christie M., additional, Barajas-Olmos, Francisco, additional, Barzilai, Nir, additional, Becker, Lewis C., additional, Bielak, Lawrence F., additional, Bis, Joshua C., additional, Blangero, John, additional, Boerwinkle, Eric, additional, Bonnycastle, Lori L., additional, Bottinger, Erwin, additional, Bowden, Donald W., additional, Bown, Matthew J., additional, Brody, Jennifer A., additional, Broome, Jai G., additional, Burtt, Noël P., additional, Cade, Brian E., additional, Centeno-Cruz, Federico, additional, Chan, Edmund, additional, Chang, Yi-Cheng, additional, Chen, Yii-Der I., additional, Cheng, Ching-Yu, additional, Choi, Won Jung, additional, Chowdhury, Rajiv, additional, Contreras-Cubas, Cecilia, additional, Córdova, Emilio J., additional, Correa, Adolfo, additional, Cupples, L. Adrienne, additional, Curran, Joanne E., additional, Danesh, John, additional, de Vries, Paul S., additional, DeFronzo, Ralph A., additional, Doddapaneni, Harsha, additional, Duggirala, Ravindranath, additional, Dutcher, Susan K., additional, Ellinor, Patrick T., additional, Emery, Leslie S., additional, Florez, Jose C., additional, Fornage, Myriam, additional, Freedman, Barry I., additional, Fuster, Valentin, additional, Garay-Sevilla, Ma. Eugenia, additional, García-Ortiz, Humberto, additional, Germer, Soren, additional, Gibbs, Richard A., additional, Gieger, Christian, additional, Glaser, Benjamin, additional, Gonzalez, Clicerio, additional, Gonzalez-Villalpando, Maria Elena, additional, Graff, Mariaelisa, additional, Graham, Sarah E., additional, Grarup, Niels, additional, Groop, Leif C., additional, Guo, Xiuqing, additional, Gupta, Namrata, additional, Han, Sohee, additional, Hanis, Craig L., additional, Hansen, Torben, additional, He, Jiang, additional, Heard-Costa, Nancy L., additional, Hung, Yi-Jen, additional, Hwang, Mi Yeong, additional, Irvin, Marguerite R., additional, Islas-Andrade, Sergio, additional, Jarvik, Gail P., additional, Kang, Hyun Min, additional, Kardia, Sharon L.R., additional, Kelly, Tanika, additional, Kenny, Eimear E., additional, Khan, Alyna T., additional, Kim, Bong-Jo, additional, Kim, Ryan W., additional, Kim, Young Jin, additional, Koistinen, Heikki A., additional, Kooperberg, Charles, additional, Kuusisto, Johanna, additional, Kwak, Soo Heon, additional, Laakso, Markku, additional, Lange, Leslie A., additional, Lee, Jiwon, additional, Lee, Juyoung, additional, Lee, Seonwook, additional, Lehman, Donna M., additional, Lemaitre, Rozenn N., additional, Linneberg, Allan, additional, Liu, Jianjun, additional, Loos, Ruth J.F., additional, Lubitz, Steven A., additional, Lyssenko, Valeriya, additional, Ma, Ronald C.W., additional, Martin, Lisa Warsinger, additional, Martínez-Hernández, Angélica, additional, Mathias, Rasika A., additional, McGarvey, Stephen T., additional, McPherson, Ruth, additional, Meigs, James B., additional, Meitinger, Thomas, additional, Melander, Olle, additional, Mendoza-Caamal, Elvia, additional, Metcalf, Ginger A., additional, Mi, Xuenan, additional, Mohlke, Karen L., additional, Montasser, May E., additional, Moon, Jee-Young, additional, Moreno-Macías, Hortensia, additional, Morrison, Alanna C., additional, Muzny, Donna M., additional, Nelson, Sarah C., additional, Nilsson, Peter M., additional, O’Connell, Jeffrey R., additional, Orho-Melander, Marju, additional, Orozco, Lorena, additional, Palmer, Colin N.A., additional, Palmer, Nicholette D., additional, Park, Cheol Joo, additional, Park, Kyong Soo, additional, Pedersen, Oluf, additional, Peralta, Juan M., additional, Peyser, Patricia A., additional, Post, Wendy S., additional, Preuss, Michael, additional, Psaty, Bruce M., additional, Qi, Qibin, additional, Rao, D.C., additional, Redline, Susan, additional, Reiner, Alexander P., additional, Revilla-Monsalve, Cristina, additional, Rich, Stephen S., additional, Samani, Nilesh, additional, Schunkert, Heribert, additional, Schurmann, Claudia, additional, Seo, Daekwan, additional, Seo, Jeong-Sun, additional, Sim, Xueling, additional, Sladek, Rob, additional, Small, Kerrin S., additional, So, Wing Yee, additional, Stilp, Adrienne M., additional, Tai, E. Shyong, additional, Tam, Claudia H.T., additional, Taylor, Kent D., additional, Teo, Yik Ying, additional, Thameem, Farook, additional, Tomlinson, Brian, additional, Tsai, Michael Y., additional, Tuomi, Tiinamaija, additional, Tuomilehto, Jaakko, additional, Tusié-Luna, Teresa, additional, Udler, Miriam S., additional, van Dam, Rob M., additional, Vasan, Ramachandran S., additional, Viaud Martinez, Karine A., additional, Wang, Fei Fei, additional, Wang, Xuzhi, additional, Watkins, Hugh, additional, Weeks, Daniel E., additional, Wilson, James G., additional, Witte, Daniel R., additional, Wong, Tien-Yin, additional, Yanek, Lisa R., additional, Kathiresan, Sekar, additional, Rader, Daniel J., additional, Rotter, Jerome I., additional, Boehnke, Michael, additional, McCarthy, Mark I., additional, Willer, Cristen J., additional, Natarajan, Pradeep, additional, Flannick, Jason A., additional, Khera, Amit V., additional, and Peloso, Gina M., additional

Published
2022
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49. Acculturation, Dietary Behaviors, and Macronutrient Intake Among Mexican Americans With Prediabetes: The Starr County Diabetes Prevention Initiative

Author

Brown, Sharon A., Becker, Heather A., García, Alexandra A., Velasquez, Mary M., Tanaka, Hirofumi, Winter, Mary A., Perkison, William B., Brown, Eric L., Aguilar, David, and Hanis, Craig L.

Abstract

Purpose: The purpose of the study was to examine the influences of sex and acculturation on dietary behaviors, macronutrient intake, and dietary quality in participants enrolled in a diabetes prevention initiative in Starr County, Texas.Methods: Baseline data from the Starr County diabetes prevention study (N = 300) were analyzed—acculturation (country of origin, years in Starr County, language and food preferences), depressive symptoms (Patient Health Questionnaire-9), healthy eating self-efficacy (Weight Efficacy Lifestyle Questionnaire-Short Form), diet quality (USDA Healthy Eating Index), fat avoidance (Fat Avoidance Scale, Spanish version), and macronutrients. Descriptive statistics and univariate analysis of covariance were used to examine differences based on acculturation, controlling for sex.Results: Participants were predominantly female (73%) and, on average, 51 years of age. Language and food preferences favored Spanish language and Hispanic foods, respectively. The majority (71%) was born in Mexico but had resided in Starr County for 33 years, on average. Depressive symptoms were moderate, and eating self-efficacy scores suggested low confidence in making healthy food choices, particularly for saturated fats. Spanish language preference was associated with worse dietary habits. The mean dietary quality score was lower than the national average (54 vs 59 nationally); females had slightly higher dietary quality than males and a higher mean fat avoidance score, although differences were not clinically significant. Intakes of carbohydrate, saturated fats, and cholesterol were higher than recommended daily allowances.Conclusions: The overall preference for speaking Spanish and the influence of language on dietary intake should inform future dietary interventions. Accommodating cultural norms and food preferences remain major challenges to improving dietary quality among the diverse Hispanic ethnic groups.

Published
2023
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