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1. Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes.

Author

Zhou, Xueya, Zhou, Xueya, Feliciano, Pamela, Shu, Chang, Wang, Tianyun, Astrovskaya, Irina, Hall, Jacob B, Obiajulu, Joseph U, Wright, Jessica R, Murali, Shwetha C, Xu, Simon Xuming, Brueggeman, Leo, Thomas, Taylor R, Marchenko, Olena, Fleisch, Christopher, Barns, Sarah D, Snyder, LeeAnne Green, Han, Bing, Chang, Timothy S, Turner, Tychele N, Harvey, William T, Nishida, Andrew, O'Roak, Brian J, Geschwind, Daniel H, SPARK Consortium, Michaelson, Jacob J, Volfovsky, Natalia, Eichler, Evan E, Shen, Yufeng, Chung, Wendy K, Zhou, Xueya, Zhou, Xueya, Feliciano, Pamela, Shu, Chang, Wang, Tianyun, Astrovskaya, Irina, Hall, Jacob B, Obiajulu, Joseph U, Wright, Jessica R, Murali, Shwetha C, Xu, Simon Xuming, Brueggeman, Leo, Thomas, Taylor R, Marchenko, Olena, Fleisch, Christopher, Barns, Sarah D, Snyder, LeeAnne Green, Han, Bing, Chang, Timothy S, Turner, Tychele N, Harvey, William T, Nishida, Andrew, O'Roak, Brian J, Geschwind, Daniel H, SPARK Consortium, Michaelson, Jacob J, Volfovsky, Natalia, Eichler, Evan E, Shen, Yufeng, and Chung, Wendy K

Abstract

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SHANK3) (59% vs 88%, P = 1.9 × 10-6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.

Published
2022

2. Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Author

Qiao, Lu, Qiao, Lu, Xu, Le, Yu, Lan, Wynn, Julia, Hernan, Rebecca, Zhou, Xueya, Farkouh-Karoleski, Christiana, Krishnan, Usha S, Khlevner, Julie, De, Aliva, Zygmunt, Annette, Crombleholme, Timothy, Lim, Foong-Yen, Needelman, Howard, Cusick, Robert A, Mychaliska, George B, Warner, Brad W, Wagner, Amy J, Danko, Melissa E, Chung, Dai, Potoka, Douglas, Kosiński, Przemyslaw, McCulley, David J, Elfiky, Mahmoud, Azarow, Kenneth, Fialkowski, Elizabeth, Schindel, David, Soffer, Samuel Z, Lyon, Jane B, Zalieckas, Jill M, Vardarajan, Badri N, Aspelund, Gudrun, Duron, Vincent P, High, Frances A, Sun, Xin, Donahoe, Patricia K, Shen, Yufeng, Chung, Wendy K, Qiao, Lu, Qiao, Lu, Xu, Le, Yu, Lan, Wynn, Julia, Hernan, Rebecca, Zhou, Xueya, Farkouh-Karoleski, Christiana, Krishnan, Usha S, Khlevner, Julie, De, Aliva, Zygmunt, Annette, Crombleholme, Timothy, Lim, Foong-Yen, Needelman, Howard, Cusick, Robert A, Mychaliska, George B, Warner, Brad W, Wagner, Amy J, Danko, Melissa E, Chung, Dai, Potoka, Douglas, Kosiński, Przemyslaw, McCulley, David J, Elfiky, Mahmoud, Azarow, Kenneth, Fialkowski, Elizabeth, Schindel, David, Soffer, Samuel Z, Lyon, Jane B, Zalieckas, Jill M, Vardarajan, Badri N, Aspelund, Gudrun, Duron, Vincent P, High, Frances A, Sun, Xin, Donahoe, Patricia K, Shen, Yufeng, and Chung, Wendy K

Abstract

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Published
2021

3. Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes.

Author

Feliciano, Pamela, Feliciano, Pamela, Zhou, Xueya, Astrovskaya, Irina, Turner, Tychele N, Wang, Tianyun, Brueggeman, Leo, Barnard, Rebecca, Hsieh, Alexander, Snyder, LeeAnne Green, Muzny, Donna M, Sabo, Aniko, SPARK Consortium, Gibbs, Richard A, Eichler, Evan E, O'Roak, Brian J, Michaelson, Jacob J, Volfovsky, Natalia, Shen, Yufeng, Chung, Wendy K, Feliciano, Pamela, Feliciano, Pamela, Zhou, Xueya, Astrovskaya, Irina, Turner, Tychele N, Wang, Tianyun, Brueggeman, Leo, Barnard, Rebecca, Hsieh, Alexander, Snyder, LeeAnne Green, Muzny, Donna M, Sabo, Aniko, SPARK Consortium, Gibbs, Richard A, Eichler, Evan E, O'Roak, Brian J, Michaelson, Jacob J, Volfovsky, Natalia, Shen, Yufeng, and Chung, Wendy K

Abstract

Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by a combination of rare de novo and inherited variants as well as common variants in at least several hundred genes. However, significantly larger sample sizes are needed to identify the complete set of genetic risk factors. We conducted a pilot study for SPARK (SPARKForAutism.org) of 457 families with ASD, all consented online. Whole exome sequencing (WES) and genotyping data were generated for each family using DNA from saliva. We identified variants in genes and loci that are clinically recognized causes or significant contributors to ASD in 10.4% of families without previous genetic findings. In addition, we identified variants that are possibly associated with ASD in an additional 3.4% of families. A meta-analysis using the TADA framework at a false discovery rate (FDR) of 0.1 provides statistical support for 26 ASD risk genes. While most of these genes are already known ASD risk genes, BRSK2 has the strongest statistical support and reaches genome-wide significance as a risk gene for ASD (p-value = 2.3e-06). Future studies leveraging the thousands of individuals with ASD who have enrolled in SPARK are likely to further clarify the genetic risk factors associated with ASD as well as allow accelerate ASD research that incorporates genetic etiology.

Published
2019

4. Mutations in Hnrnpa1 cause congenital heart defects.

Author

Yu, Zhe, Yu, Zhe, Tang, Paul Lf, Wang, Jing, Bao, Suying, Shieh, Joseph T, Leung, Alan Wl, Zhang, Zhao, Gao, Fei, Wong, Sandra Yy, Hui, Andy Lc, Gao, Yuan, Dung, Nelson, Zhang, Zhi-Gang, Fan, Yanhui, Zhou, Xueya, Zhang, Yalun, Wong, Dana Sm, Sham, Pak C, Azhar, Abid, Kwok, Pui-Yan, Tam, Patrick Pl, Lian, Qizhou, Cheah, Kathryn Se, Wang, Binbin, Song, You-Qiang, Yu, Zhe, Yu, Zhe, Tang, Paul Lf, Wang, Jing, Bao, Suying, Shieh, Joseph T, Leung, Alan Wl, Zhang, Zhao, Gao, Fei, Wong, Sandra Yy, Hui, Andy Lc, Gao, Yuan, Dung, Nelson, Zhang, Zhi-Gang, Fan, Yanhui, Zhou, Xueya, Zhang, Yalun, Wong, Dana Sm, Sham, Pak C, Azhar, Abid, Kwok, Pui-Yan, Tam, Patrick Pl, Lian, Qizhou, Cheah, Kathryn Se, Wang, Binbin, and Song, You-Qiang

Abstract

Incomplete penetrance of congenital heart defects (CHDs) was observed in a mouse model. We hypothesized that the contribution of a major genetic locus modulates the manifestation of the CHDs. After genome-wide linkage mapping, fine mapping, and high-throughput targeted sequencing, a recessive frameshift mutation of the heterogeneous nuclear ribonucleoprotein A1 (Hnrnpa1) gene was confirmed (Hnrnpa1ct). Hnrnpa1 was expressed in both the first heart field (FHF) and second heart field (SHF) at the cardiac crescent stage but was only maintained in SHF progenitors after heart tube formation. Hnrnpa1ct/ct homozygous mutants displayed complete CHD penetrance, including truncated and incomplete looped heart tube at E9.5, ventricular septal defect (VSD) and persistent truncus arteriosus (PTA) at E13.5, and VSD and double outlet right ventricle at P0. Impaired development of the dorsal mesocardium and sinoatrial node progenitors was also observed. Loss of Hnrnpa1 expression leads to dysregulation of cardiac transcription networks and multiple signaling pathways, including BMP, FGF, and Notch in the SHF. Finally, two rare heterozygous mutations of HNRNPA1 were detected in human CHDs. These findings suggest a role of Hnrnpa1 in embryonic heart development in mice and humans.

Published
2018

5. Mutations in Hnrnpa1 cause congenital heart defects.

Author

Yu, Zhe, Yu, Zhe, Tang, Paul Lf, Wang, Jing, Bao, Suying, Shieh, Joseph T, Leung, Alan Wl, Zhang, Zhao, Gao, Fei, Wong, Sandra Yy, Hui, Andy Lc, Gao, Yuan, Dung, Nelson, Zhang, Zhi-Gang, Fan, Yanhui, Zhou, Xueya, Zhang, Yalun, Wong, Dana Sm, Sham, Pak C, Azhar, Abid, Kwok, Pui-Yan, Tam, Patrick Pl, Lian, Qizhou, Cheah, Kathryn Se, Wang, Binbin, Song, You-Qiang, Yu, Zhe, Yu, Zhe, Tang, Paul Lf, Wang, Jing, Bao, Suying, Shieh, Joseph T, Leung, Alan Wl, Zhang, Zhao, Gao, Fei, Wong, Sandra Yy, Hui, Andy Lc, Gao, Yuan, Dung, Nelson, Zhang, Zhi-Gang, Fan, Yanhui, Zhou, Xueya, Zhang, Yalun, Wong, Dana Sm, Sham, Pak C, Azhar, Abid, Kwok, Pui-Yan, Tam, Patrick Pl, Lian, Qizhou, Cheah, Kathryn Se, Wang, Binbin, and Song, You-Qiang

Abstract

Incomplete penetrance of congenital heart defects (CHDs) was observed in a mouse model. We hypothesized that the contribution of a major genetic locus modulates the manifestation of the CHDs. After genome-wide linkage mapping, fine mapping, and high-throughput targeted sequencing, a recessive frameshift mutation of the heterogeneous nuclear ribonucleoprotein A1 (Hnrnpa1) gene was confirmed (Hnrnpa1ct). Hnrnpa1 was expressed in both the first heart field (FHF) and second heart field (SHF) at the cardiac crescent stage but was only maintained in SHF progenitors after heart tube formation. Hnrnpa1ct/ct homozygous mutants displayed complete CHD penetrance, including truncated and incomplete looped heart tube at E9.5, ventricular septal defect (VSD) and persistent truncus arteriosus (PTA) at E13.5, and VSD and double outlet right ventricle at P0. Impaired development of the dorsal mesocardium and sinoatrial node progenitors was also observed. Loss of Hnrnpa1 expression leads to dysregulation of cardiac transcription networks and multiple signaling pathways, including BMP, FGF, and Notch in the SHF. Finally, two rare heterozygous mutations of HNRNPA1 were detected in human CHDs. These findings suggest a role of Hnrnpa1 in embryonic heart development in mice and humans.

Published
2018

6. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Author

Kato, Norihiro, Loh, Marie, Takeuchi, Fumihiko, Verweij, Niek, Wang, Xu, Zhang, Weihua, Kelly, Tanika N., Saleheen, Danish, Lehne, Benjamin, Leach, Irene Mateo, Drong, Alexander W., Abbott, James, Wahl, Simone, Tan, Sian-Tsung, Scott, William R., Campanella, Gianluca, Chadeau-Hyam, Marc, Afzal, Uzma, Ahluwalia, Tarunveer S., Bonder, Marc Jan, Chen, Peng, Dehghan, Abbas, Edwards, Todd L., Esko, Tonu, Go, Min Jin, Harris, Sarah E., Hartiala, Jaana, Kasela, Silva, Kasturiratne, Anuradhani, Khor, Chiea-Chuen, Kleber, Marcus E., Li, Huaixing, Mok, Zuan Yu, Nakatochi, Masahiro, Sapari, Nur Sabrina, Saxena, Richa, Stewart, Alexandre F. R., Stolk, Lisette, Tabara, Yasuharu, Teh, Ai Ling, Wu, Ying, Wu, Jer-Yuarn, Zhang, Yi, Aits, Imke, Alves, Alexessander Da Silva Couto, Das, Shikta, Dorajoo, Rajkumar, Hopewell, Jemma C., Kim, Yun Kyoung, Koivula, Robert W., Luan, Jian'an, Lyytikainen, Leo-Pekka, Nguyen, Quang N., Pereira, Mark A., Postmus, Iris, Raitakari, Olli T., Bryan, Molly Scannell, Scott, Robert A., Sorice, Rossella, Tragante, Vinicius, Traglia, Michela, White, Jon, Yamamoto, Ken, Zhang, Yonghong, Adair, Linda S., Ahmed, Alauddin, Akiyama, Koichi, Asif, Rasheed, Aung, Tin, Barroso, Ines, Bjonnes, Andrew, Braun, Timothy R., Cai, Hui, Chang, Li-Ching, Chen, Chien-Hsiun, Cheng, Ching-Yu, Chong, Yap-Seng, Collins, Rory, Courtney, Regina, Davies, Gail, Delgado, Graciela, Do, Loi D., Doevendans, Pieter A., Gansevoort, Ron T., Gao, Yu-Tang, Grammer, Tanja B., Grarup, Niels, Grewal, Jagvir, Gu, Dongfeng, Wander, Gurpreet S., Hartikainen, Anna-Liisa, Hazen, Stanley L., He, Jing, Heng, Chew-Kiat, Hixson, James E., Hofman, Albert, Hsu, Chris, Huang, Wei, Husemoen, Lise L. N., Hwang, Joo-Yeon, Ichihara, Sahoko, Igase, Michiya, Isono, Masato, Justesen, Johanne M., Katsuy, Tomohiro, Kibriya, Muhammad G., Kim, Young Jin, Kishimoto, Miyako, Koh, Woon-Puay, Kohara, Katsuhiko, Kumari, Meena, Kwek, Kenneth, Lee, Nanette R., Lee, Jeannette, Liao, Jiemin, Lieb, Wolfgang, Liewald, David C. M., Matsubara, Tatsuaki, Matsushita, Yumi, Meitinger, Thomas, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Mononen, Nina, Mueller-Nurasyid, Martina, Nabika, Toru, Nakashima, Eitaro, Ng, Hong Kiat, Nikus, Kjell, Nutile, Teresa, Ohkubo, Takayoshi, Ohnaka, Keizo, Parish, Sarah, Paternoster, Lavinia, Peng, Hao, Peters, Annette, Pham, Son T., Pinidiyapathirage, Mohitha J., Rahman, Mahfuzar, Rakugi, Hiromi, Rolandsson, Olov, Rozario, Michelle Ann, Ruggiero, Daniela, Sala, Cinzia F., Sarju, Ralhan, Shimokawa, Kazuro, Snieder, Harold, Sparso, Thomas, Spiering, Wilko, Starr, John M., Stott, David J., Stram, Daniel O., Sugiyama, Takao, Szymczak, Silke, Tang, W. H. Wilson, Tong, Lin, Trompet, Stella, Turjanmaa, Vaino, Ueshima, Hirotsugu, Uitterlinden, Andre G., Umemura, Satoshi, Vaarasmaki, Marja, van Dam, Rob M., van Gilst, Wiek H., van Veldhuisen, Dirk J., Viikari, Jorma S., Waldenberger, Melanie, Wang, Yiqin, Wang, Aili, Wilson, Rory, Wong, Tien-Yin, Xiang, Yong-Bing, Yamaguchi, Shuhei, Ye, Xingwang, Young, Robin D., Young, Terri L., Yuan, Jian-Min, Zhou, Xueya, Asselbergs, Folkert W., Ciullo, Marina, Clarke, Robert, Deloukas, Panos, Franke, Andre, Franks, Paul W, Franks, Steve, Friedlander, Yechiel, Gross, Myron D., Guo, Zhirong, Hansen, Torben, Jarvelin, Marjo-Riitta, Jorgensen, Torben, Jukema, J. Wouter, Kahonen, Mika, Kajio, Hiroshi, Kivimaki, Mika, Lee, Jong-Young, Lehtimaki, Terho, Linneberg, Allan, Miki, Tetsuro, Pedersen, Oluf, Samani, Nilesh J., Sorensen, Thorkild I. A., Takayanagi, Ryoichi, Toniolo, Daniela, Ahsan, Habibul, Allayee, Hooman, Chen, Yuan-Tsong, Danesh, John, Deary, Ian J., Franco, Oscar H., Franke, Lude, Heijman, Bastiaan T., Holbrook, Joanna D., Isaacs, Aaron, Kim, Bong-Jo, Lin, Xu, Liu, Jianjun, Maerz, Winfried, Metspalu, Andres, Mohlke, Karen L., Sanghera, Dharambir K., Shu, Xiao-Ou, van Meurs, Joyce B. J., Vithana, Eranga, Wickremasinghe, Ananda R., Wijmenga, Cisca, Wolffenbuttel, Bruce H. W., Yokota, Mitsuhiro, Zheng, Wei, Zhu, Dingliang, Vineis, Paolo, Kyrtopoulos, Soterios A., Kleinjans, Jos C. S., McCarthy, Mark I., Soong, Richie, Gieger, Christian, Scott, James, Teo, Yik-Ying, He, Jiang, Elliott, Paul, Tai, E. Shyong, van der Harst, Pim, Kooner, Jaspal S., Chambers, John C., Kato, Norihiro, Loh, Marie, Takeuchi, Fumihiko, Verweij, Niek, Wang, Xu, Zhang, Weihua, Kelly, Tanika N., Saleheen, Danish, Lehne, Benjamin, Leach, Irene Mateo, Drong, Alexander W., Abbott, James, Wahl, Simone, Tan, Sian-Tsung, Scott, William R., Campanella, Gianluca, Chadeau-Hyam, Marc, Afzal, Uzma, Ahluwalia, Tarunveer S., Bonder, Marc Jan, Chen, Peng, Dehghan, Abbas, Edwards, Todd L., Esko, Tonu, Go, Min Jin, Harris, Sarah E., Hartiala, Jaana, Kasela, Silva, Kasturiratne, Anuradhani, Khor, Chiea-Chuen, Kleber, Marcus E., Li, Huaixing, Mok, Zuan Yu, Nakatochi, Masahiro, Sapari, Nur Sabrina, Saxena, Richa, Stewart, Alexandre F. R., Stolk, Lisette, Tabara, Yasuharu, Teh, Ai Ling, Wu, Ying, Wu, Jer-Yuarn, Zhang, Yi, Aits, Imke, Alves, Alexessander Da Silva Couto, Das, Shikta, Dorajoo, Rajkumar, Hopewell, Jemma C., Kim, Yun Kyoung, Koivula, Robert W., Luan, Jian'an, Lyytikainen, Leo-Pekka, Nguyen, Quang N., Pereira, Mark A., Postmus, Iris, Raitakari, Olli T., Bryan, Molly Scannell, Scott, Robert A., Sorice, Rossella, Tragante, Vinicius, Traglia, Michela, White, Jon, Yamamoto, Ken, Zhang, Yonghong, Adair, Linda S., Ahmed, Alauddin, Akiyama, Koichi, Asif, Rasheed, Aung, Tin, Barroso, Ines, Bjonnes, Andrew, Braun, Timothy R., Cai, Hui, Chang, Li-Ching, Chen, Chien-Hsiun, Cheng, Ching-Yu, Chong, Yap-Seng, Collins, Rory, Courtney, Regina, Davies, Gail, Delgado, Graciela, Do, Loi D., Doevendans, Pieter A., Gansevoort, Ron T., Gao, Yu-Tang, Grammer, Tanja B., Grarup, Niels, Grewal, Jagvir, Gu, Dongfeng, Wander, Gurpreet S., Hartikainen, Anna-Liisa, Hazen, Stanley L., He, Jing, Heng, Chew-Kiat, Hixson, James E., Hofman, Albert, Hsu, Chris, Huang, Wei, Husemoen, Lise L. N., Hwang, Joo-Yeon, Ichihara, Sahoko, Igase, Michiya, Isono, Masato, Justesen, Johanne M., Katsuy, Tomohiro, Kibriya, Muhammad G., Kim, Young Jin, Kishimoto, Miyako, Koh, Woon-Puay, Kohara, Katsuhiko, Kumari, Meena, Kwek, Kenneth, Lee, Nanette R., Lee, Jeannette, Liao, Jiemin, Lieb, Wolfgang, Liewald, David C. M., Matsubara, Tatsuaki, Matsushita, Yumi, Meitinger, Thomas, Mihailov, Evelin, Milani, Lili, Mills, Rebecca, Mononen, Nina, Mueller-Nurasyid, Martina, Nabika, Toru, Nakashima, Eitaro, Ng, Hong Kiat, Nikus, Kjell, Nutile, Teresa, Ohkubo, Takayoshi, Ohnaka, Keizo, Parish, Sarah, Paternoster, Lavinia, Peng, Hao, Peters, Annette, Pham, Son T., Pinidiyapathirage, Mohitha J., Rahman, Mahfuzar, Rakugi, Hiromi, Rolandsson, Olov, Rozario, Michelle Ann, Ruggiero, Daniela, Sala, Cinzia F., Sarju, Ralhan, Shimokawa, Kazuro, Snieder, Harold, Sparso, Thomas, Spiering, Wilko, Starr, John M., Stott, David J., Stram, Daniel O., Sugiyama, Takao, Szymczak, Silke, Tang, W. H. Wilson, Tong, Lin, Trompet, Stella, Turjanmaa, Vaino, Ueshima, Hirotsugu, Uitterlinden, Andre G., Umemura, Satoshi, Vaarasmaki, Marja, van Dam, Rob M., van Gilst, Wiek H., van Veldhuisen, Dirk J., Viikari, Jorma S., Waldenberger, Melanie, Wang, Yiqin, Wang, Aili, Wilson, Rory, Wong, Tien-Yin, Xiang, Yong-Bing, Yamaguchi, Shuhei, Ye, Xingwang, Young, Robin D., Young, Terri L., Yuan, Jian-Min, Zhou, Xueya, Asselbergs, Folkert W., Ciullo, Marina, Clarke, Robert, Deloukas, Panos, Franke, Andre, Franks, Paul W, Franks, Steve, Friedlander, Yechiel, Gross, Myron D., Guo, Zhirong, Hansen, Torben, Jarvelin, Marjo-Riitta, Jorgensen, Torben, Jukema, J. Wouter, Kahonen, Mika, Kajio, Hiroshi, Kivimaki, Mika, Lee, Jong-Young, Lehtimaki, Terho, Linneberg, Allan, Miki, Tetsuro, Pedersen, Oluf, Samani, Nilesh J., Sorensen, Thorkild I. A., Takayanagi, Ryoichi, Toniolo, Daniela, Ahsan, Habibul, Allayee, Hooman, Chen, Yuan-Tsong, Danesh, John, Deary, Ian J., Franco, Oscar H., Franke, Lude, Heijman, Bastiaan T., Holbrook, Joanna D., Isaacs, Aaron, Kim, Bong-Jo, Lin, Xu, Liu, Jianjun, Maerz, Winfried, Metspalu, Andres, Mohlke, Karen L., Sanghera, Dharambir K., Shu, Xiao-Ou, van Meurs, Joyce B. J., Vithana, Eranga, Wickremasinghe, Ananda R., Wijmenga, Cisca, Wolffenbuttel, Bruce H. W., Yokota, Mitsuhiro, Zheng, Wei, Zhu, Dingliang, Vineis, Paolo, Kyrtopoulos, Soterios A., Kleinjans, Jos C. S., McCarthy, Mark I., Soong, Richie, Gieger, Christian, Scott, James, Teo, Yik-Ying, He, Jiang, Elliott, Paul, Tai, E. Shyong, van der Harst, Pim, Kooner, Jaspal S., and Chambers, John C.

Abstract

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Published
2015
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7. Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index

Author

Wen, Wanqing, Wen, Wanqing, Zheng, Wei, Okada, Yukinori, Takeuchi, Fumihiko, Tabara, Yasuharu, Hwang, Joo-Yeon, Dorajoo, Rajkumar, Li, Huaixing, Tsai, Fuu-Jen, Yang, Xiaobo, He, Jiang, Wu, Ying, He, Meian, Zhang, Yi, Liang, Jun, Guo, Xiuqing, Sheu, Wayne Huey-Herng, Delahanty, Ryan, Guo, Xingyi, Kubo, Michiaki, Yamamoto, Ken, Ohkubo, Takayoshi, Go, Min Jin, Liu, Jian Jun, Gan, Wei, Chen, Ching-Chu, Gao, Yong, Li, Shengxu, Lee, Nanette R, Wu, Chen, Zhou, Xueya, Song, Huaidong, Yao, Jie, Lee, I-Te, Long, Jirong, Tsunoda, Tatsuhiko, Akiyama, Koichi, Takashima, Naoyuki, Cho, Yoon Shin, Ong, Rick TH, Lu, Ling, Chen, Chien-Hsiun, Tan, Aihua, Rice, Treva K, Adair, Linda S, Gui, Lixuan, Allison, Matthew, Lee, Wen-Jane, Cai, Qiuyin, Isomura, Minoru, Umemura, Satoshi, Kim, Young Jin, Seielstad, Mark, Hixson, James, Xiang, Yong-Bing, Isono, Masato, Kim, Bong-Jo, Sim, Xueling, Lu, Wei, Nabika, Toru, Lee, Juyoung, Lim, Wei-Yen, Gao, Yu-Tang, Takayanagi, Ryoichi, Kang, Dae-Hee, Wong, Tien Yin, Hsiung, Chao Agnes, Wu, I-Chien, Juang, Jyh-Ming Jimmy, Shi, Jiajun, Choi, Bo Youl, Aung, Tin, Hu, Frank, Kim, Mi Kyung, Lim, Wei Yen, Wang, Tzung-Dao, Shin, Min-Ho, Lee, Jeannette, Ji, Bu-Tian, Lee, Young-Hoon, Young, Terri L, Shin, Dong Hoon, Chun, Byung-Yeol, Cho, Myeong-Chan, Han, Bok-Ghee, Hwu, Chii-Min, Assimes, Themistocles L, Absher, Devin, Yan, Xiaofei, Kim, Eric, Kuo, Jane Z, Kwon, Soonil, Taylor, Kent D, Chen, Yii-Der I, Rotter, Jerome I, Qi, Lu, Zhu, Dingliang, Wu, Tangchun, Mohlke, Karen L, Gu, Dongfeng, Wen, Wanqing, Wen, Wanqing, Zheng, Wei, Okada, Yukinori, Takeuchi, Fumihiko, Tabara, Yasuharu, Hwang, Joo-Yeon, Dorajoo, Rajkumar, Li, Huaixing, Tsai, Fuu-Jen, Yang, Xiaobo, He, Jiang, Wu, Ying, He, Meian, Zhang, Yi, Liang, Jun, Guo, Xiuqing, Sheu, Wayne Huey-Herng, Delahanty, Ryan, Guo, Xingyi, Kubo, Michiaki, Yamamoto, Ken, Ohkubo, Takayoshi, Go, Min Jin, Liu, Jian Jun, Gan, Wei, Chen, Ching-Chu, Gao, Yong, Li, Shengxu, Lee, Nanette R, Wu, Chen, Zhou, Xueya, Song, Huaidong, Yao, Jie, Lee, I-Te, Long, Jirong, Tsunoda, Tatsuhiko, Akiyama, Koichi, Takashima, Naoyuki, Cho, Yoon Shin, Ong, Rick TH, Lu, Ling, Chen, Chien-Hsiun, Tan, Aihua, Rice, Treva K, Adair, Linda S, Gui, Lixuan, Allison, Matthew, Lee, Wen-Jane, Cai, Qiuyin, Isomura, Minoru, Umemura, Satoshi, Kim, Young Jin, Seielstad, Mark, Hixson, James, Xiang, Yong-Bing, Isono, Masato, Kim, Bong-Jo, Sim, Xueling, Lu, Wei, Nabika, Toru, Lee, Juyoung, Lim, Wei-Yen, Gao, Yu-Tang, Takayanagi, Ryoichi, Kang, Dae-Hee, Wong, Tien Yin, Hsiung, Chao Agnes, Wu, I-Chien, Juang, Jyh-Ming Jimmy, Shi, Jiajun, Choi, Bo Youl, Aung, Tin, Hu, Frank, Kim, Mi Kyung, Lim, Wei Yen, Wang, Tzung-Dao, Shin, Min-Ho, Lee, Jeannette, Ji, Bu-Tian, Lee, Young-Hoon, Young, Terri L, Shin, Dong Hoon, Chun, Byung-Yeol, Cho, Myeong-Chan, Han, Bok-Ghee, Hwu, Chii-Min, Assimes, Themistocles L, Absher, Devin, Yan, Xiaofei, Kim, Eric, Kuo, Jane Z, Kwon, Soonil, Taylor, Kent D, Chen, Yii-Der I, Rotter, Jerome I, Qi, Lu, Zhu, Dingliang, Wu, Tangchun, Mohlke, Karen L, and Gu, Dongfeng

Abstract

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.

Published
2014

8. Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.

Author

Wen, Wanqing, Wen, Wanqing, Zheng, Wei, Okada, Yukinori, Takeuchi, Fumihiko, Tabara, Yasuharu, Hwang, Joo-Yeon, Dorajoo, Rajkumar, Li, Huaixing, Tsai, Fuu-Jen, Yang, Xiaobo, He, Jiang, Wu, Ying, He, Meian, Zhang, Yi, Liang, Jun, Guo, Xiuqing, Sheu, Wayne Huey-Herng, Delahanty, Ryan, Guo, Xingyi, Kubo, Michiaki, Yamamoto, Ken, Ohkubo, Takayoshi, Go, Min Jin, Liu, Jian Jun, Gan, Wei, Chen, Ching-Chu, Gao, Yong, Li, Shengxu, Lee, Nanette R, Wu, Chen, Zhou, Xueya, Song, Huaidong, Yao, Jie, Lee, I-Te, Long, Jirong, Tsunoda, Tatsuhiko, Akiyama, Koichi, Takashima, Naoyuki, Cho, Yoon Shin, Ong, Rick Th, Lu, Ling, Chen, Chien-Hsiun, Tan, Aihua, Rice, Treva K, Adair, Linda S, Gui, Lixuan, Allison, Matthew, Lee, Wen-Jane, Cai, Qiuyin, Isomura, Minoru, Umemura, Satoshi, Kim, Young Jin, Seielstad, Mark, Hixson, James, Xiang, Yong-Bing, Isono, Masato, Kim, Bong-Jo, Sim, Xueling, Lu, Wei, Nabika, Toru, Lee, Juyoung, Lim, Wei-Yen, Gao, Yu-Tang, Takayanagi, Ryoichi, Kang, Dae-Hee, Wong, Tien Yin, Hsiung, Chao Agnes, Wu, I-Chien, Juang, Jyh-Ming Jimmy, Shi, Jiajun, Choi, Bo Youl, Aung, Tin, Hu, Frank, Kim, Mi Kyung, Lim, Wei Yen, Wang, Tzung-Dao, Shin, Min-Ho, Lee, Jeannette, Ji, Bu-Tian, Lee, Young-Hoon, Young, Terri L, Shin, Dong Hoon, Chun, Byung-Yeol, Cho, Myeong-Chan, Han, Bok-Ghee, Hwu, Chii-Min, Assimes, Themistocles L, Absher, Devin, Yan, Xiaofei, Kim, Eric, Kuo, Jane Z, Kwon, Soonil, Taylor, Kent D, Chen, Yii-Der I, Rotter, Jerome I, Qi, Lu, Zhu, Dingliang, Wu, Tangchun, Mohlke, Karen L, Gu, Dongfeng, Wen, Wanqing, Wen, Wanqing, Zheng, Wei, Okada, Yukinori, Takeuchi, Fumihiko, Tabara, Yasuharu, Hwang, Joo-Yeon, Dorajoo, Rajkumar, Li, Huaixing, Tsai, Fuu-Jen, Yang, Xiaobo, He, Jiang, Wu, Ying, He, Meian, Zhang, Yi, Liang, Jun, Guo, Xiuqing, Sheu, Wayne Huey-Herng, Delahanty, Ryan, Guo, Xingyi, Kubo, Michiaki, Yamamoto, Ken, Ohkubo, Takayoshi, Go, Min Jin, Liu, Jian Jun, Gan, Wei, Chen, Ching-Chu, Gao, Yong, Li, Shengxu, Lee, Nanette R, Wu, Chen, Zhou, Xueya, Song, Huaidong, Yao, Jie, Lee, I-Te, Long, Jirong, Tsunoda, Tatsuhiko, Akiyama, Koichi, Takashima, Naoyuki, Cho, Yoon Shin, Ong, Rick Th, Lu, Ling, Chen, Chien-Hsiun, Tan, Aihua, Rice, Treva K, Adair, Linda S, Gui, Lixuan, Allison, Matthew, Lee, Wen-Jane, Cai, Qiuyin, Isomura, Minoru, Umemura, Satoshi, Kim, Young Jin, Seielstad, Mark, Hixson, James, Xiang, Yong-Bing, Isono, Masato, Kim, Bong-Jo, Sim, Xueling, Lu, Wei, Nabika, Toru, Lee, Juyoung, Lim, Wei-Yen, Gao, Yu-Tang, Takayanagi, Ryoichi, Kang, Dae-Hee, Wong, Tien Yin, Hsiung, Chao Agnes, Wu, I-Chien, Juang, Jyh-Ming Jimmy, Shi, Jiajun, Choi, Bo Youl, Aung, Tin, Hu, Frank, Kim, Mi Kyung, Lim, Wei Yen, Wang, Tzung-Dao, Shin, Min-Ho, Lee, Jeannette, Ji, Bu-Tian, Lee, Young-Hoon, Young, Terri L, Shin, Dong Hoon, Chun, Byung-Yeol, Cho, Myeong-Chan, Han, Bok-Ghee, Hwu, Chii-Min, Assimes, Themistocles L, Absher, Devin, Yan, Xiaofei, Kim, Eric, Kuo, Jane Z, Kwon, Soonil, Taylor, Kent D, Chen, Yii-Der I, Rotter, Jerome I, Qi, Lu, Zhu, Dingliang, Wu, Tangchun, Mohlke, Karen L, and Gu, Dongfeng

Abstract

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.

Published
2014

9. Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index

Author

Wen Wanqing, Zheng Wei, Okada Yukinori, Takeuchi Fumihiko, Tabara Yasuharu, Hwang Joo-Yeon, Dorajoo Rajkumar, Li Huaixing, Tsai Fuu-Jen, Yang Xiaobo, He Jiang, Wu Ying, He Meian, Zhang Yi, Liang Jun, Guo Xiuqing, Sheu Wayne Huey-Herng, Delahanty Ryan, Guo Xingyi, Kubo Michiaki, Yamamoto Ken, Ohkubo Takayoshi, Go Min Jin, Liu Jian Jun, Gan Wei, Chen Ching-Chu, Gao Yong, Li Shengxu, Lee Nanette R., Wu Chen, Zhou Xueya, Song Huaidong, Yao Jie, Lee I-Te, Long Jirong, Tsunoda Tatsuhiko, Akiyama Koichi, Takashima Naoyuki, Cho Yoon Shin, Ong Rick T. H., Lu Ling, Chen Chien-Hsiun, Tan Aihua, Rice Treva K., Adair Linda S., Gui Lixuan, Allison Matthew, Lee Wen-Jane, Cai Qiuyin, ISOMURA, Minoru, Umemura Satoshi, Kim Young Jin, Seielstad Mark, Hixson James, Xiang Yong-Bing, Isono Masato, Kim Bong-Jo, Sim Xueling, Lu Wei, Nabika, Toru, Lee Juyoung, Lim Wei-Yen, Gao Yu-Tang, Takayanagi Ryoichi, Kang Dae-Hee, Wong Tien Yin, Hsiung ChaoAgnes, Wu I-Chien, Juang Jyh-Ming Jimmy, Shi Jiajun, Choi Bo Youl, Aung Tin, Hu Frank, Kim Mi Kyung, Lim WeiYen, Wang Tzung-Dao, Shin Min-Ho, Lee Jeannette, Ji Bu-Tian, Lee Young-Hoon, Young Terri L., Shin Dong Hoon, Chun Byung-Yeol, Cho Myeong-Chan, Han Bok-Ghee, Hwu Chii-Min, Assimes Themistocles L., Absher Devin, Yan Xiaofei, Kim Eric, Kuo Jane Z., Kwon Soonil, Taylor Kent D., Chen Yii-Der I., Rotter Jerome I., Qi Lu, Zhu Dingliang, Wu Tangchun, Mohlke Karen L., Gu Dongfeng, Mo Zengnan, Wu Jer-Yuarn, Lin Xu, Miki Tetsuro, Tai E. Shyong, Lee Jong-Young, Kato Norihiro, Shu Xiao-Ou, Tanaka Toshihiro, Wen Wanqing, Zheng Wei, Okada Yukinori, Takeuchi Fumihiko, Tabara Yasuharu, Hwang Joo-Yeon, Dorajoo Rajkumar, Li Huaixing, Tsai Fuu-Jen, Yang Xiaobo, He Jiang, Wu Ying, He Meian, Zhang Yi, Liang Jun, Guo Xiuqing, Sheu Wayne Huey-Herng, Delahanty Ryan, Guo Xingyi, Kubo Michiaki, Yamamoto Ken, Ohkubo Takayoshi, Go Min Jin, Liu Jian Jun, Gan Wei, Chen Ching-Chu, Gao Yong, Li Shengxu, Lee Nanette R., Wu Chen, Zhou Xueya, Song Huaidong, Yao Jie, Lee I-Te, Long Jirong, Tsunoda Tatsuhiko, Akiyama Koichi, Takashima Naoyuki, Cho Yoon Shin, Ong Rick T. H., Lu Ling, Chen Chien-Hsiun, Tan Aihua, Rice Treva K., Adair Linda S., Gui Lixuan, Allison Matthew, Lee Wen-Jane, Cai Qiuyin, ISOMURA, Minoru, Umemura Satoshi, Kim Young Jin, Seielstad Mark, Hixson James, Xiang Yong-Bing, Isono Masato, Kim Bong-Jo, Sim Xueling, Lu Wei, Nabika, Toru, Lee Juyoung, Lim Wei-Yen, Gao Yu-Tang, Takayanagi Ryoichi, Kang Dae-Hee, Wong Tien Yin, Hsiung ChaoAgnes, Wu I-Chien, Juang Jyh-Ming Jimmy, Shi Jiajun, Choi Bo Youl, Aung Tin, Hu Frank, Kim Mi Kyung, Lim WeiYen, Wang Tzung-Dao, Shin Min-Ho, Lee Jeannette, Ji Bu-Tian, Lee Young-Hoon, Young Terri L., Shin Dong Hoon, Chun Byung-Yeol, Cho Myeong-Chan, Han Bok-Ghee, Hwu Chii-Min, Assimes Themistocles L., Absher Devin, Yan Xiaofei, Kim Eric, Kuo Jane Z., Kwon Soonil, Taylor Kent D., Chen Yii-Der I., Rotter Jerome I., Qi Lu, Zhu Dingliang, Wu Tangchun, Mohlke Karen L., Gu Dongfeng, Mo Zengnan, Wu Jer-Yuarn, Lin Xu, Miki Tetsuro, Tai E. Shyong, Lee Jong-Young, Kato Norihiro, Shu Xiao-Ou, and Tanaka Toshihiro

Published
2014

10. Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.

Author

Wen, Wanqing, Wen, Wanqing, Zheng, Wei, Okada, Yukinori, Takeuchi, Fumihiko, Tabara, Yasuharu, Hwang, Joo-Yeon, Dorajoo, Rajkumar, Li, Huaixing, Tsai, Fuu-Jen, Yang, Xiaobo, He, Jiang, Wu, Ying, He, Meian, Zhang, Yi, Liang, Jun, Guo, Xiuqing, Sheu, Wayne Huey-Herng, Delahanty, Ryan, Guo, Xingyi, Kubo, Michiaki, Yamamoto, Ken, Ohkubo, Takayoshi, Go, Min Jin, Liu, Jian Jun, Gan, Wei, Chen, Ching-Chu, Gao, Yong, Li, Shengxu, Lee, Nanette R, Wu, Chen, Zhou, Xueya, Song, Huaidong, Yao, Jie, Lee, I-Te, Long, Jirong, Tsunoda, Tatsuhiko, Akiyama, Koichi, Takashima, Naoyuki, Cho, Yoon Shin, Ong, Rick Th, Lu, Ling, Chen, Chien-Hsiun, Tan, Aihua, Rice, Treva K, Adair, Linda S, Gui, Lixuan, Allison, Matthew, Lee, Wen-Jane, Cai, Qiuyin, Isomura, Minoru, Umemura, Satoshi, Kim, Young Jin, Seielstad, Mark, Hixson, James, Xiang, Yong-Bing, Isono, Masato, Kim, Bong-Jo, Sim, Xueling, Lu, Wei, Nabika, Toru, Lee, Juyoung, Lim, Wei-Yen, Gao, Yu-Tang, Takayanagi, Ryoichi, Kang, Dae-Hee, Wong, Tien Yin, Hsiung, Chao Agnes, Wu, I-Chien, Juang, Jyh-Ming Jimmy, Shi, Jiajun, Choi, Bo Youl, Aung, Tin, Hu, Frank, Kim, Mi Kyung, Lim, Wei Yen, Wang, Tzung-Dao, Shin, Min-Ho, Lee, Jeannette, Ji, Bu-Tian, Lee, Young-Hoon, Young, Terri L, Shin, Dong Hoon, Chun, Byung-Yeol, Cho, Myeong-Chan, Han, Bok-Ghee, Hwu, Chii-Min, Assimes, Themistocles L, Absher, Devin, Yan, Xiaofei, Kim, Eric, Kuo, Jane Z, Kwon, Soonil, Taylor, Kent D, Chen, Yii-Der I, Rotter, Jerome I, Qi, Lu, Zhu, Dingliang, Wu, Tangchun, Mohlke, Karen L, Gu, Dongfeng, Wen, Wanqing, Wen, Wanqing, Zheng, Wei, Okada, Yukinori, Takeuchi, Fumihiko, Tabara, Yasuharu, Hwang, Joo-Yeon, Dorajoo, Rajkumar, Li, Huaixing, Tsai, Fuu-Jen, Yang, Xiaobo, He, Jiang, Wu, Ying, He, Meian, Zhang, Yi, Liang, Jun, Guo, Xiuqing, Sheu, Wayne Huey-Herng, Delahanty, Ryan, Guo, Xingyi, Kubo, Michiaki, Yamamoto, Ken, Ohkubo, Takayoshi, Go, Min Jin, Liu, Jian Jun, Gan, Wei, Chen, Ching-Chu, Gao, Yong, Li, Shengxu, Lee, Nanette R, Wu, Chen, Zhou, Xueya, Song, Huaidong, Yao, Jie, Lee, I-Te, Long, Jirong, Tsunoda, Tatsuhiko, Akiyama, Koichi, Takashima, Naoyuki, Cho, Yoon Shin, Ong, Rick Th, Lu, Ling, Chen, Chien-Hsiun, Tan, Aihua, Rice, Treva K, Adair, Linda S, Gui, Lixuan, Allison, Matthew, Lee, Wen-Jane, Cai, Qiuyin, Isomura, Minoru, Umemura, Satoshi, Kim, Young Jin, Seielstad, Mark, Hixson, James, Xiang, Yong-Bing, Isono, Masato, Kim, Bong-Jo, Sim, Xueling, Lu, Wei, Nabika, Toru, Lee, Juyoung, Lim, Wei-Yen, Gao, Yu-Tang, Takayanagi, Ryoichi, Kang, Dae-Hee, Wong, Tien Yin, Hsiung, Chao Agnes, Wu, I-Chien, Juang, Jyh-Ming Jimmy, Shi, Jiajun, Choi, Bo Youl, Aung, Tin, Hu, Frank, Kim, Mi Kyung, Lim, Wei Yen, Wang, Tzung-Dao, Shin, Min-Ho, Lee, Jeannette, Ji, Bu-Tian, Lee, Young-Hoon, Young, Terri L, Shin, Dong Hoon, Chun, Byung-Yeol, Cho, Myeong-Chan, Han, Bok-Ghee, Hwu, Chii-Min, Assimes, Themistocles L, Absher, Devin, Yan, Xiaofei, Kim, Eric, Kuo, Jane Z, Kwon, Soonil, Taylor, Kent D, Chen, Yii-Der I, Rotter, Jerome I, Qi, Lu, Zhu, Dingliang, Wu, Tangchun, Mohlke, Karen L, and Gu, Dongfeng

Abstract

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.

Published
2014

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