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1. DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood

Author

Prachand Issarapu, Manisha Arumalla, Hannah R. Elliott, Suraj S. Nongmaithem, Alagu Sankareswaran, Modupeh Betts, Sara Sajjadi, Noah J. Kessler, Swati Bayyana, Sohail R. Mansuri, Maria Derakhshan, G. V. Krishnaveni, Smeeta Shrestha, Kalyanaraman Kumaran, Chiara Di Gravio, Sirazul A. Sahariah, Eleanor Sanderson, Caroline L. Relton, Kate A. Ward, Sophie E. Moore, Andrew M. Prentice, Karen A. Lillycrop, Caroline H. D. Fall, Matt J. Silver, Giriraj R. Chandak, and the EMPHASIS study group

Subjects
Science
Abstract

Abstract Human height is strongly influenced by genetics but the contribution of modifiable epigenetic factors is under-explored, particularly in low and middle-income countries (LMIC). We investigate links between blood DNA methylation and child height in four LMIC cohorts (n = 1927) and identify a robust association at three CpGs in the suppressor of cytokine signaling 3 (SOCS3) gene which replicates in a high-income country cohort (n = 879). SOCS3 methylation (SOCS3m)—height associations are independent of genetic effects. Mendelian randomization analysis confirms a causal effect of SOCS3m on height. In longitudinal analysis, SOCS3m explains a maximum 9.5% of height variance in mid-childhood while the variance explained by height polygenic risk score increases from birth to 21 years. Children’s SOCS3m is associated with prenatal maternal folate and socio-economic status. In-vitro characterization confirms a regulatory effect of SOCS3m on gene expression. Our findings suggest epigenetic modifications may play an important role in driving child height in LMIC.

Published
2023
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2. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Stavroula Kanoni, Sarah E. Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L. Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W. Winkler, Adam E. Locke, Eirini Marouli, Greg J. M. Zajac, Kuan-Han H. Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T. Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F. Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M. Brumpton, Humaira Rasheed, Aki S. Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A. Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J. Kullo, Akira Narita, Jun Takayama, Hilary C. Martin, Karen A. Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E. Miller, Archie Campbell, Kuang Lin, Iona Y. Millwood, Asif Rasheed, George Hindy, Jessica D. Faul, Wei Zhao, David R. Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R. Brown, Weihua Zhang, Ketian Yu, Ellen M. Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian’an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R. Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A. Yousri, Ruth E. Mitchell, Jin Fang Chai, Mette Aadahl, Anne A. Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R. Warren, Julia Ramirez, Jette Bork-Jensen, Line L. Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F. McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T. Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E. Galesloot, Jonathan P. Bradfield, Sanni E. Ruotsalainen, EWarwick Daw, Joseph M. Zmuda, Jonathan S. Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A. Brody, Miguel Vazquez-Moreno, Mary F. Feitosa, Mary K. Wojczynski, Zhe Wang, Michael H. Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W. Benjamins, Jorgen Engmann, Noah L. Tsao, Anurag Verma, Roderick C. Slieker, Ken Sin Lo, Nuno R. Zilhao, Phuong Le, Marcus E. Kleber, Graciela E. Delgado, Shaofeng Huo, Daisuke D. Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L. Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J. Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S. Nongmaithem, Swati Bayyana, Heather M. Stringham, Marguerite R. Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R. H. J. Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A. Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N. Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C. Warner, Ya Xing Wang, Wen B. Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A. Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F. Bielak, Jennifer A. Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J. van der Most, Niina Pitkänen, Brian E. Cade, Sander W. van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R. Bentley, Ayo P. Doumatey, Adebowale A. Adeyemo, Jong Young Lee, Eva R. B. Petersen, Aneta A. Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W. Rayner, Carol A. Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O. Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D. Jackson, Alexander P. Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C. Bis, Lenore J. Launer, Huaixing Li, Mike A. Nalls, Olli T. Raitakari, Sahoko Ichihara, Sarah H. Wild, Christopher P. Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S. Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J. de Borst, Eung Kweon Kim, Hieab H. H. Adams, M. Arfan Ikram, Xiaofeng Zhu, Folkert W. Asselbergs, Adriaan O. Kraaijeveld, Joline W. J. Beulens, Xiao-Ou Shu, Loukianos S. Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W. Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E. Pennell, Trevor A. Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M. Heid, Klaus J. Stark, Martina E. Zimmermann, Henry Völzke, Georg Homuth, Michele K. Evans, Alan B. Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E. Hoefer, Susan Redline, Katja Pahkala, Albertine J. Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L. R. Kardia, Patricia A. Peyser, Norihiro Kato, Matthias B. Schulze, Giorgia Girotto, Carsten A. Böger, Bettina Jung, Peter K. Joshi, David A. Bennett, Philip L. De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J. Caulfield, Patricia B. Munroe, Xiuqing Guo, Marina Ciullo, Jost B. Jonas, Nilesh J. Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A. Aguilar-Salinas, Linda S. Adair, Sonny Augustin Bechayda, H. Janaka de Silva, Ananda R. Wickremasinghe, Ronald M. Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G. Wilson, Lars Lind, Chew-Kiat Heng, Amanda E. Nelson, Yvonne M. Golightly, James F. Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J. Scott, D. C. Rao, Donna K. Arnett, Steven C. Hunt, Mark Walker, Heikki A. Koistinen, Giriraj R. Chandak, Josep M. Mercader, Maria C. Costanzo, Dongkeun Jang, Noël P. Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M. van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F. Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I. McCarthy, Colin N. A. Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M. van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M.‘t Hart, Petra J. M. Elders, Scott M. Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D. Spector, Ruth J. F. Loos, Michael A. Province, Esteban J. Parra, Miguel Cruz, Bruce M. Psaty, Ivan Brandslund, Peter P. Pramstaller, Charles N. Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F. A. Grant, Lambertus A. L. M. Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W. Franks, Allan Linneberg, J. Wouter Jukema, Amit V. Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O. Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P. Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I. Rotter, Thomas M. Dantoft, Fredrik Karpe, Matt J. Neville, Nicholas J. Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T. Hattersley, Nancy L. Pedersen, Patrik K. E. Magnusson, Dorret I. Boomsma, Allegonda H. M. Willemsen, LAdrienne Cupples, Joyce B. J. van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J. Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C. Chambers, Jaspal S. Kooner, Paul S. de Vries, Alanna C. Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E. North, Martha Daviglus, Peter Kraft, Nicholas G. Martin, John B. Whitfield, Shahid Abbas, Danish Saleheen, Robin G. Walters, Michael V. Holmes, Corri Black, Blair H. Smith, Aris Baras, Anne E. Justice, Julie E. Buring, Paul M. Ridker, Daniel I. Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A. van Heel, Richard C. Trembath, Wei-Qi Wei, Gail P. Jarvik, Bahram Namjou, M. Geoffrey Hayes, Marylyn D. Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A. Lynch, Daniel J. Rader, Philip S. Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J. O’Donnell, John M. Gaziano, Peter W. F. Wilson, Timothy M. Frayling, Joel N. Hirschhorn, Sekar Kathiresan, Karen L. Mohlke, Yan V. Sun, Andrew P. Morris, Michael Boehnke, Christopher D. Brown, Pradeep Natarajan, Panos Deloukas, Cristen J. Willer, Themistocles L. Assimes, and Gina M. Peloso

Subjects
Cholesterol, Lipids, Genetics, Genome-wide association study, GWAS, Biology (General), QH301-705.5, QH426-470
Abstract

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

Published
2022
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3. Sexual dimorphism in the relationship between brain complexity, volume and general intelligence (g): a cross-cohort study

Author

Anca-Larisa Sandu, Gordon D. Waiter, Roger T. Staff, Nafeesa Nazlee, Tina Habota, Chris J. McNeil, Dorota Chapko, Justin H. Williams, Caroline H. D. Fall, Giriraj R. Chandak, Shailesh Pene, Murali Krishna, Andrew M. McIntosh, Heather C. Whalley, Kalyanaraman Kumaran, Ghattu V. Krishnaveni, and Alison D. Murray

Subjects
Medicine, Science
Abstract

Abstract Changes in brain morphology have been reported during development, ageing and in relation to different pathologies. Brain morphology described by the shape complexity of gyri and sulci can be captured and quantified using fractal dimension (FD). This measure of brain structural complexity, as well as brain volume, are associated with intelligence, but less is known about the sexual dimorphism of these relationships. In this paper, sex differences in the relationship between brain structural complexity and general intelligence (g) in two diverse geographic and cultural populations (UK and Indian) are investigated. 3D T1-weighted magnetic resonance imaging (MRI) data and a battery of cognitive tests were acquired from participants belonging to three different cohorts: Mysore Parthenon Cohort (MPC); Aberdeen Children of the 1950s (ACONF) and UK Biobank. We computed MRI derived structural brain complexity and g estimated from a battery of cognitive tests for each group. Brain complexity and volume were both positively corelated with intelligence, with the correlations being significant in women but not always in men. This relationship is seen across populations of differing ages and geographical locations and improves understanding of neurobiological sex-differences.

Published
2022
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4. Identification of genetic effects underlying type 2 diabetes in South Asian and European populations

Author

Marie Loh, Weihua Zhang, Hong Kiat Ng, Katharina Schmid, Amel Lamri, Lin Tong, Meraj Ahmad, Jung-Jin Lee, Maggie C. Y. Ng, Lauren E. Petty, Cassandra N. Spracklen, Fumihiko Takeuchi, Md. Tariqul Islam, Farzana Jasmine, Anuradhani Kasturiratne, Muhammad Kibriya, Karen L. Mohlke, Guillaume Paré, Gauri Prasad, Mohammad Shahriar, Miao Ling Chee, H. Janaka de Silva, James C. Engert, Hertzel C. Gerstein, K. Radha Mani, Charumathi Sabanayagam, Marijana Vujkovic, Ananda R. Wickremasinghe, Tien Yin Wong, Chittaranjan S. Yajnik, Salim Yusuf, Habibul Ahsan, Dwaipayan Bharadwaj, Sonia S. Anand, Jennifer E. Below, Michael Boehnke, Donald W. Bowden, Giriraj R. Chandak, Ching-Yu Cheng, Norihiro Kato, Anubha Mahajan, Xueling Sim, Mark I. McCarthy, Andrew P. Morris, Jaspal S. Kooner, Danish Saleheen, and John C. Chambers

Subjects
Biology (General), QH301-705.5
Abstract

Marie Loh, Weihua Zhang et al. use a genome-wide association study meta-analysis to examine variants associated with Type 2 diabetes (T2D) in South Asian and European ancestry cohorts. Their results provide further insights into the genetic mechanisms underlying T2D across ancestral populations.

Published
2022
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5. The REVAMP study: research exploring various aspects and mechanisms in preeclampsia: study protocol

Author

Nisha S. Wadhwani, Deepali P. Sundrani, Girija N. Wagh, Savita S. Mehendale, Manish M. Tipnis, Priscilla C. Joshi, Arun S. Kinare, Sanjay K. Lalwani, Narayanan S. Mani, Nomita Chandhiok, Giriraj R. Chandak, Sanjay A. Gupte, Caroline H. D. Fall, and Sadhana R. Joshi

Subjects
Preeclampsia, Long chain polyunsaturated fatty acids, Developmental programming, Gynecology and obstetrics, RG1-991
Abstract

Abstract Background Preeclampsia is a major cause of maternal, fetal and neonatal morbidity and mortality, particularly in developing countries. Considering the burden of preeclampsia and its associated complications, it is important to understand the underlying risk factors and mechanisms involved in its etiology. There is considerable interest in the potential for dietary long chain polyunsaturated fatty acids (LCPUFA) as a therapeutic intervention to prevent preeclampsia, as they are involved in angiogenesis, oxidative stress, and inflammatory pathways. Methods The REVAMP study (Research Exploring Various Aspects and Mechanisms in Preeclampsia) follows a cohort of pregnant women from early pregnancy until delivery to examine longitudinally the associations of maternal LCPUFA with clinical outcome in preeclampsia. A multisite centre for advanced research was established and pregnant women coming to Bharati hospital and Gupte hospital, Pune, India for their first antenatal visit are recruited and followed up at 11–14 weeks, 18–22 weeks, 26–28 weeks, and at delivery. Their personal, obstetric, clinical, and family history are recorded. Anthropometric measures (height, weight), food frequency questionnaire (FFQ), physical activity, socioeconomic status, fetal ultrasonography, and color Doppler measures are recorded at different time points across gestation. Maternal blood at all time points, cord blood, and placenta at delivery are collected, processed and stored at − 80 °C. The children’s anthropometry is assessed serially up to the age of 2 years, when their neurodevelopmental scores will be assessed. Discussion This study will help in early identification of pregnant women who are at risk of developing preeclampsia. The prospective design of the study for the first time will establish the role of LCPUFA in understanding the underlying biochemical and molecular mechanisms involved in preeclampsia and their association with developmental programming in children.

Published
2019
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6. Author Correction: Identification of genetic effects underlying type 2 diabetes in South Asian and European populations

Author

Marie Loh, Weihua Zhang, Hong Kiat Ng, Katharina Schmid, Amel Lamri, Lin Tong, Meraj Ahmad, Jung-Jin Lee, Maggie C. Y. Ng, Lauren E. Petty, Cassandra N. Spracklen, Fumihiko Takeuchi, Md. Tariqul Islam, Farzana Jasmine, Anuradhani Kasturiratne, Muhammad Kibriya, Karen L. Mohlke, Guillaume Paré, Gauri Prasad, Mohammad Shahriar, Miao Ling Chee, H. Janaka de Silva, James C. Engert, Hertzel C. Gerstein, K. Radha Mani, Charumathi Sabanayagam, Marijana Vujkovic, Ananda R. Wickremasinghe, Tien Yin Wong, Chittaranjan S. Yajnik, Salim Yusuf, Habibul Ahsan, Dwaipayan Bharadwaj, Sonia S. Anand, Jennifer E. Below, Michael Boehnke, Donald W. Bowden, Giriraj R. Chandak, Ching-Yu Cheng, Norihiro Kato, Anubha Mahajan, Xueling Sim, Mark I. McCarthy, Andrew P. Morris, Jaspal S. Kooner, Danish Saleheen, and John C. Chambers

Subjects
Biology (General), QH301-705.5
Published
2022
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7. Genetic Architecture of Parkinson's Disease in the Indian Population: Harnessing Genetic Diversity to Address Critical Gaps in Parkinson's Disease Research

Author

Roopa Rajan, K. P. Divya, Rukmini Mridula Kandadai, Ravi Yadav, Venkata P. Satagopam, U. K. Madhusoodanan, Pankaj Agarwal, Niraj Kumar, Teresa Ferreira, Hrishikesh Kumar, A. V. Sreeram Prasad, Kuldeep Shetty, Sahil Mehta, Soaham Desai, Suresh Kumar, L. K. Prashanth, Mohit Bhatt, Pettarusp Wadia, Sudha Ramalingam, G. M. Wali, Sanjay Pandey, Felix Bartusch, Maximilian Hannussek, Jens Krüger, Ashwin Kumar-Sreelatha, Sandeep Grover, Peter Lichtner, Marc Sturm, Jochen Roeper, Volker Busskamp, Giriraj R. Chandak, Jens Schwamborn, Pankaj Seth, Thomas Gasser, Olaf Riess, Vinay Goyal, Pramod Kumar Pal, Rupam Borgohain, Rejko Krüger, Asha Kishore, Manu Sharma, and The Lux-GIANT Consortium

Subjects
Parkinson's disease, genetic diversity, genome-wide association study, common genetic variation, biobank, Neurology. Diseases of the nervous system, RC346-429
Abstract

Over the past two decades, our understanding of Parkinson's disease (PD) has been gleaned from the discoveries made in familial and/or sporadic forms of PD in the Caucasian population. The transferability and the clinical utility of genetic discoveries to other ethnically diverse populations are unknown. The Indian population has been under-represented in PD research. The Genetic Architecture of PD in India (GAP-India) project aims to develop one of the largest clinical/genomic bio-bank for PD in India. Specifically, GAP-India project aims to: (1) develop a pan-Indian deeply phenotyped clinical repository of Indian PD patients; (2) perform whole-genome sequencing in 500 PD samples to catalog Indian genetic variability and to develop an Indian PD map for the scientific community; (3) perform a genome-wide association study to identify novel loci for PD and (4) develop a user-friendly web-portal to disseminate results for the scientific community. Our “hub-spoke” model follows an integrative approach to develop a pan-Indian outreach to develop a comprehensive cohort for PD research in India. The alignment of standard operating procedures for recruiting patients and collecting biospecimens with international standards ensures harmonization of data/bio-specimen collection at the beginning and also ensures stringent quality control parameters for sample processing. Data sharing and protection policies follow the guidelines established by local and national authorities.We are currently in the recruitment phase targeting recruitment of 10,200 PD patients and 10,200 healthy volunteers by the end of 2020. GAP-India project after its completion will fill a critical gap that exists in PD research and will contribute a comprehensive genetic catalog of the Indian PD population to identify novel targets for PD.

Published
2020
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8. Protocol for the EMPHASIS study; epigenetic mechanisms linking maternal pre-conceptional nutrition and children’s health in India and Sub-Saharan Africa

Author

Giriraj R. Chandak, Matt J. Silver, Ayden Saffari, Karen A. Lillycrop, Smeeta Shrestha, Sirazul Ameen Sahariah, Chiara Di Gravio, Gail Goldberg, Ashutosh Singh Tomar, Modupeh Betts, Sara Sajjadi, Lena Acolatse, Philip James, Prachand Issarapu, Kalyanaraman Kumaran, Ramesh D. Potdar, Andrew M. Prentice, Caroline H. D. Fall, the EMPHASIS study group, Meraj Ahmed, Harsha Chopra, Cyrus Cooper, Momodou K. Darboe, Meera Gandhi, Gail R. Goldberg, Ramatoulie Janha, Landing M. A. Jarjou, Lovejeet Kaur, Sarah H. Kehoe, Mohammed Ngum, Suraj S. Nongmaithem, Stephen Owens, Ann Prentice, Tallapragada Divya Sri Priyanka, Harshad Sane, Kate A. Ward, Dilip Kumar Yadav, and Chittaranjan S. Yajnik

Subjects
Pre- and peri-conceptional nutrition, Epigenetics, DNA methylation, Children, Growth, Body composition, Nutrition. Foods and food supply, TX341-641, Food processing and manufacture, TP368-456, Medicine (General), R5-920
Abstract

Abstract Background Animal studies have shown that nutritional exposures during pregnancy can modify epigenetic marks regulating fetal development and susceptibility to later disease, providing a plausible mechanism to explain the developmental origins of health and disease. Human observational studies have shown that maternal peri-conceptional diet predicts DNA methylation in offspring. However, a causal pathway from maternal diet, through changes in DNA methylation, to later health outcomes has yet to be established. The EMPHASIS study (Epigenetic Mechanisms linking Pre-conceptional nutrition and Health Assessed in India and Sub-Saharan Africa, ISRCTN14266771) will investigate epigenetically mediated links between peri-conceptional nutrition and health-related outcomes in children whose mothers participated in two randomized controlled trials of micronutrient supplementation before and during pregnancy. Methods The original trials were the Mumbai Maternal Nutrition Project (MMNP, ISRCTN62811278) in which Indian women were offered a daily snack made from micronutrient-rich foods or low-micronutrient foods (controls), and the Peri-conceptional Multiple Micronutrient Supplementation Trial (PMMST, ISRCTN13687662) in rural Gambia, in which women were offered a daily multiple micronutrient (UNIMMAP) tablet or placebo. In the EMPHASIS study, DNA methylation will be analysed in the children of these women (~1100 children aged 5–7 y in MMNP and 298 children aged 7–9 y in PMMST). Cohort-specific and cross-cohort effects will be explored. Differences in DNA methylation between allocation groups will be identified using the Illumina Infinium MethylationEPIC array, and by pyrosequencing top hits and selected candidate loci. Associations will be analysed between DNA methylation and health-related phenotypic outcomes, including size at birth, and children’s post-natal growth, body composition, skeletal development, cardio-metabolic risk markers (blood pressure, serum lipids, plasma glucose and insulin) and cognitive function. Pathways analysis will be used to test for enrichment of nutrition-sensitive loci in biological pathways. Causal mechanisms for nutrition-methylation-phenotype associations will be explored using Mendelian Randomization. Associations between methylation unrelated to supplementation and phenotypes will also be analysed. Conclusion The study will increase understanding of the epigenetic mechanisms underpinning the long-term impact of maternal nutrition on offspring health. It will potentially lead to better nutritional interventions for mothers preparing for pregnancy, and to identification of early life biomarkers of later disease risk.

Published
2017
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9. Inclusion of Population-specific Reference Panel from India to the 1000 Genomes Phase 3 Panel Improves Imputation Accuracy

Author

Meraj Ahmad, Anubhav Sinha, Sreya Ghosh, Vikrant Kumar, Sonia Davila, Chittaranjan S. Yajnik, and Giriraj R. Chandak

Subjects
Medicine, Science
Abstract

Abstract Imputation is a computational method based on the principle of haplotype sharing allowing enrichment of genome-wide association study datasets. It depends on the haplotype structure of the population and density of the genotype data. The 1000 Genomes Project led to the generation of imputation reference panels which have been used globally. However, recent studies have shown that population-specific panels provide better enrichment of genome-wide variants. We compared the imputation accuracy using 1000 Genomes phase 3 reference panel and a panel generated from genome-wide data on 407 individuals from Western India (WIP). The concordance of imputed variants was cross-checked with next-generation re-sequencing data on a subset of genomic regions. Further, using the genome-wide data from 1880 individuals, we demonstrate that WIP works better than the 1000 Genomes phase 3 panel and when merged with it, significantly improves the imputation accuracy throughout the minor allele frequency range. We also show that imputation using only South Asian component of the 1000 Genomes phase 3 panel works as good as the merged panel, making it computationally less intensive job. Thus, our study stresses that imputation accuracy using 1000 Genomes phase 3 panel can be further improved by including population-specific reference panels from South Asia.

Published
2017
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10. Differential expression of genes influencing mitotic processes in cord blood mononuclear cells after a pre-conceptional micronutrient-based randomised controlled trial: Pune Rural Intervention in Young Adolescents (PRIYA)

Author

Satyajeet P. Khare, Ayush Madhok, Indumathi Patta, Krishna K. Sukla, Vipul V. Wagh, Pooja S. Kunte, Deepa Raut, Dattatray Bhat, Kalyanaraman Kumaran, Caroline Fall, Utpal Tatu, Giriraj R. Chandak, Chittaranjan S. Yajnik, and Sanjeev Galande

Subjects
Medicine (miscellaneous)
Abstract

In The Pune Maternal Nutrition Study, vitamin B12 deficiency was seen in 65% of pregnant women, folate deficiency was rare. Maternal total homocysteine concentrations were inversely associated with offspring birthweight, and low vitamin B12 and high folate concentrations predicted higher offspring adiposity and insulin resistance. These findings guided a nested pre-conceptional randomised controlled trial ‘Pune Rural Intervention in Young Adolescents’. The interventions included: (1) vitamin B12+multi-micronutrients as per the United Nations International Multiple Micronutrient Antenatal Preparation, and proteins (B12+MMN), (2) vitamin B12 (B12 alone), and (3) placebo. Intervention improved maternal pre-conceptional and in-pregnancy micronutrient nutrition. Gene expression analysis in cord blood mononuclear cells in 88 pregnancies revealed 75 differentially expressed genes between the B12+MMN and placebo groups. The enriched biological processes included G2/M phase transition, chromosome segregation, and nuclear division. Enriched pathways included, mitotic spindle checkpoint and DNA damage response while enriched human phenotypes were sloping forehead and decreased head circumference. Fructose-bisphosphatase 2 (FBP2) and Cell Division Cycle Associated 2 (CDCA2) genes were under-expressed in the B12 alone group. The latter, involved in chromosome segregation was under-expressed in both intervention groups. Based on the role of B-complex vitamins in the synthesis of nucleotides and S-adenosyl methionine, and the roles of vitamins A and D on gene expression, we propose that the multi-micronutrient intervention epigenetically affected cell cycle dynamics. Neonates in the B12+MMN group had the highest ponderal index. Follow-up studies will reveal if the intervention and the altered biological processes influence offspring diabesity.

Published
2023

11. Maternal diabetes influences neonatal obesity-adiposity but not in later life Offspring obesity in diabetic pregnancy

Author

Sayali S. Deshpande-Joshi, Sonali S. Wagle, Madhura K. Deshmukh, Hemant S. Damle, Suhas R. Otiv, Sanat B. Phatak, Smita N. Dhadge, Shubha S. Ambardekar, Dattatray S. Bhat, Deepa A. Raut, Rajashree P. Kamat, Sayali G. Wadke, Kalyanaraman Kumaran, Giriraj R. Chandak, and Chittaranjan S. Yajnik

Abstract

BackgroundBased on studies in overweight-obese populations, it is tacitly assumed that maternal hyperglycemia is responsible for obesity-adiposity at birth and in later life.Study designTwo hospital based case control studies: 1) Neonatal outcomes, 2) Later life outcomes.MethodsWe studied associations of neonatal and later life obesity-adiposity [age and sex-adjusted BMI, waist circumference, skinfolds, and body fat percent by Dual energy X-ray Absorptiometry (DXA)] in offspring of mothers with diabetes (ODM) and those of mothers without diabetes (ONDM). Exposures were parental hyperglycemia and overweight-obesity.ResultsNeonatal study included 372 non-diabetic and 816 diabetic pregnancies [74 type 1 diabetes, 102 type 2 diabetes, 640 gestational diabetes (GDM)]. Mothers with type 1 diabetes were the youngest, thinnest, and with highest HbA1c. Maternal glycemia but not BMI was associated with neonatal obesity-adiposity. Thus, neonates of mothers with type 1 diabetes had highest ponderal index, abdominal circumference, and skinfolds.Later life study included 200 ODM (25 type 1 diabetes, 22 type 2 diabetes, 153 GDM) and 177 age, sex and socio-economic matched ONDM (2 to 26 y). Their obesity-adiposity was associated with bi-parental overweight-obesity in an additive manner, but not with parental diabetes. Offspring birth weight was also positively associated. Offspring of mothers with type 1 diabetes had the lowest and offspring of mothers with type 2 diabetes the highest obesity-adiposity.ConclusionNeonatal obesity-adiposity is driven by maternal glycemia while later life obesity-adiposity by bi-parental obesity. Our results provide a clear insight into pathogenesis of obesity-adiposity in the offspring.Article HighlightsIt is tacitly assumed that maternal diabetes is responsible for offspring obesity-adiposity.We examined the determinants of obesity-adiposity in intrauterine and in later life in children born to mothers with type 1, type 2 and GDM. Paternal influence was also investigated.Mothers with type 1 diabetes were the thinnest and most hyperglycemic. Their children were the most obese-adipose at birth but thinnest in later life. Later life obesity-adiposity was driven by bi-parental overweight-obesity, not by diabetes.Our findings suggest that strict maternal metabolic control during pregnancy will reduce macrosomia while targeting obesogenic family environment may reduce later life offspring obesity-adiposity.

Published
2023

13. Tissue- and ethnicity-independent hypervariable DNA methylation states show evidence of establishment in the early human embryo

Author

Maria Derakhshan, Noah J Kessler, Miho Ishida, Charalambos Demetriou, Nicolas Brucato, Gudrun E Moore, Caroline H D Fall, Giriraj R Chandak, Francois-Xavier Ricaut, Andrew M Prentice, Garrett Hellenthal, Matt J Silver, Evolution et Diversité Biologique (EDB), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Medical Research Council, Human Genetics Division [Singapore], Genome Institute of Singapore (GIS), and University College of London [London] (UCL)

Subjects
Tissue-and ethnicity-independent, Illumina 450K array, Hypervariable DNA methylation, Genetics, Early embryo, Humans, Reproducibility of Results, Systemic inter-individual variation, [SDE.BE]Environmental Sciences/Biodiversity and Ecology, DNA Methylation
Abstract

We analysed DNA methylation data from 30 datasets comprising 3474 individuals, 19 tissues and 8 ethnicities at CpGs covered by the Illumina450K array. We identified 4143 hypervariable CpGs (‘hvCpGs’) with methylation in the top 5% most variable sites across multiple tissues and ethnicities. hvCpG methylation was influenced but not determined by genetic variation, and was not linked to probe reliability, epigenetic drift, age, sex or cell heterogeneity effects. hvCpG methylation tended to covary across tissues derived from different germ-layers and hvCpGs were enriched for proximity to ERV1 and ERVK retrovirus elements. hvCpGs were also enriched for loci previously associated with periconceptional environment, parent-of-origin-specific methylation, and distinctive methylation signatures in monozygotic twins. Together, these properties position hvCpGs as strong candidates for studying how stochastic and/or environmentally influenced DNA methylation states which are established in the early embryo and maintained stably thereafter can influence life-long health and disease.

Published
2022

14. Size at birth, lifecourse factors and cognitive function in late life: Findings from the MYsore study of Natal effects on Ageing and Health (MYNAH) cohort in South India

Author

Ghattu V. Krishnaveni, Mohan Kumar, Caroline H.D. Fall, Murali Krishna, Giriraj R. Chandak, Kalyanaraman Kumaran, Clive Osmond, Kiran Nagaraj, Patsy J. Coakley, Veena Sargur, Samuel Chirstaprasad Karat, Mathew Varghese, and Martin Prince

Subjects
business.industry, Birth weight, Cognition, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Diabetes mellitus, Cohort, medicine, Geriatrics and Gerontology, business, Gerontology, Stroke, Socioeconomic status, Body mass index, Depression (differential diagnoses), Demography
Abstract

Objective:To examine if smaller size at birth, an indicator of growth restriction in utero, is associated with lower cognition in late life, and whether this may be mediated by impaired early life brain development and/or adverse cardiometabolic programming.Design:Longitudinal follow-up of a birth cohort.Setting:CSI Holdsworth Memorial Hospital (HMH), Mysore South India.Participants:721 men and women (55–80 years) whose size at birth was recorded at HMH. Approximately 20 years earlier, a subset (n = 522) of them had assessments for cardiometabolic disorders in mid-life.Measurements:Standardized measurement of cognitive function, depression, sociodemographic, and lifestyle factors; blood tests and assessments for cardiometabolic disordersResults:Participants who were heavier at birth had higher composite cognitive scores (0.12 SD per SD birth weight [95% CI 0.05, 0.19] p = 0.001) in late life. Other lifecourse factors independently positively related to cognition were maternal educational level and participants’ own educational level, adult leg length, body mass index, and socioeconomic position, and negatively were diabetes in mid-life and current depression and stroke. The association of birth weight with cognition was independent cardiometabolic risk factors and was attenuated after adjustment for all lifecourse factors (0.08 SD per SD birth weight [95% CI −0.01, 0.18] p = 0.07).Conclusions:The findings are consistent with positive effects of early life environmental factors (better fetal growth, education, and childhood socioeconomic status) on brain development resulting in greater long-term cognitive function. The results do not support a pathway linking poorer fetal development with reduced late life cognitive function through cardiometabolic programming.

Published
2022

15. Placental growth factor and Fms related tyrosine kinase-1 are hypomethylated in preeclampsia placentae

Author

Kinjal M Dave, Deepali P. Sundrani, Karuna Randhir, Sadhana Joshi, Lovejeet Kaur, Savita Mehendale, and Giriraj R. Chandak

Subjects
Adult, 0301 basic medicine, Placental growth factor, Cancer Research, Angiogenesis, Placenta, Receptor, Macrophage Colony-Stimulating Factor, Biology, Preeclampsia, Andrology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Pre-Eclampsia, Pregnancy, Genetics, medicine, Humans, Gene, reproductive and urinary physiology, Placenta Growth Factor, Vascular Endothelial Growth Factor Receptor-1, 030219 obstetrics & reproductive medicine, Base Sequence, dNaM, DNA Methylation, medicine.disease, female genital diseases and pregnancy complications, 030104 developmental biology, medicine.anatomical_structure, Case-Control Studies, embryonic structures, DNA methylation, Female, Tyrosine kinase
Abstract

Aim: This study aims to examine the DNA methylation (DNAm) and expression patterns of genes associated with placental angiogenesis in preeclampsia. Materials & methods: DNAm and expression were examined in normotensive (n = 100) and preeclampsia (n = 100) women using pyrosequencing and quantitative real-time PCR respectively. Results: Hypomethylation at several CpGs was observed in PlGF and FLT-1 in women with preeclampsia compared to normotensive controls. PlGF expression was lower in women with preeclampsia while FLT-1 expression was comparable. DNAm at various CpGs was negatively correlated with expression in both the genes and were associated with maternal blood pressure and birth outcomes. Conclusion: DNAm and expression of angiogenic factors in placentae are differentially regulated in preeclampsia and influence birth outcomes.

Published
2021

16. Effect of maternal preconceptional and pregnancy micronutrient interventions on children’s DNA methylation: Findings from the EMPHASIS study

Author

Sara Sajjadi, Dilip K. Yadav, Matt J. Silver, Karen A. Lillycrop, Sirazul A. Sahariah, Philip James, Kalyanaraman Kumaran, Ayden Saffari, Ashutosh Singh Tomar, Modupeh Betts, Giriraj R. Chandak, Caroline H.D. Fall, Prachand Issarapu, Smeeta Shrestha, Andrew M. Prentice, and Akshay Dedaniya

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Offspring, Quantitative Trait Loci, Psychological intervention, Medicine (miscellaneous), law.invention, AcademicSubjects/MED00160, AcademicSubjects/MED00060, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Pregnancy, law, medicine, Humans, Micronutrients, micronutrient intervention, Child, Randomized Controlled Trials as Topic, DNA methylation, Nutrition and Dietetics, Prenatal nutrition, epigenetics, Obstetrics, business.industry, dNaM, Maternal Nutritional Physiological Phenomena, epigenome-wide association study, medicine.disease, Micronutrient, Neoplasm Proteins, Original Research Communications, 030104 developmental biology, Child, Preschool, Cohort, Female, Gene-Environment Interaction, Proteoglycans, business, RCT, 030217 neurology & neurosurgery
Abstract

Background: Maternal nutrition in pregnancy has been linked to offspring health in early and later life, with changes to DNA methylation (DNAm) proposed as a mediating mechanism. Objective: We investigated intervention-associated DNAm changes in children whose mothers participated in 2 randomized controlled trials of micronutrient supplementation before and during pregnancy, as part of the EMPHASIS (Epigenetic Mechanisms linking Preconceptional nutrition and Health Assessed in India and sub-Saharan Africa) study (ISRCTN14266771). Design: We conducted epigenome-wide association studies with blood samples from Indian (n = 698) and Gambian (n = 293) children using the Illumina EPIC array and a targeted study of selected loci not on the array. The Indian micronutrient intervention was food based, whereas the Gambian intervention was a micronutrient tablet. Results: We identified 6 differentially methylated CpGs in Gambians [2.5-5.0% reduction in intervention group, all false discovery rate (FDR)

Published
2020

17. Environmentally sensitive hotspots in the methylome of the early human embryo

Author

Matt J. Silver, Ayden Saffari, Noah J. Kessler, Giriraj R. Chandak, Caroline H.D. Fall, Prachand Issarapu, Akshay Dedaniya, Modupeh Betts, Sophie E. Moore, Michael N. Routledge, Zdenko Herceg, Cyrille Cuenin, Maria Derakhshan, Philip T. James, David Monk, Andrew M. Prentice, Silver, Matt J [0000-0002-3852-9677], and Apollo - University of Cambridge Repository

Subjects
ADN, global health, Disease, Biology, Methylation, Germline, General Biochemistry, Genetics and Molecular Biology, Epigenesis, Genetic, 03 medical and health sciences, Epigenome, 0302 clinical medicine, early embryo, genomics, Humans, genetics, Epigenetics, Enhancer, Child, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, General Immunology and Microbiology, General Neuroscience, Genetic variants, Genetics and Genomics, Embryo, DNA, General Medicine, metastable epiallele, DNA Methylation, Embryo, Mammalian, Epidemiology and Global Health, nutrition, Evolutionary biology, 030220 oncology & carcinogenesis, Fertilization, DNA methylation, epidemiology, CpG Islands, conception, parent-of-origin effects, Metilació, Research Article, Human
Abstract

In humans, DNA methylation marks inherited from gametes are largely erased following fertilisation, prior to construction of the embryonic methylome. Exploiting a natural experiment of seasonal variation including changes in diet and nutritional status in rural Gambia, we analysed three datasets covering two independent child cohorts and identified 259 CpGs showing consistent associations between season of conception (SoC) and DNA methylation. SoC effects were most apparent in early infancy, with evidence of attenuation by mid-childhood. SoC-associated CpGs were enriched for metastable epialleles, parent-of-origin-specific methylation and germline differentially methylated regions, supporting a periconceptional environmental influence. Many SoC-associated CpGs overlapped enhancers or sites of active transcription in H1 embryonic stem cells and fetal tissues. Half were influenced but not determined by measured genetic variants that were independent of SoC. Environmental ‘hotspots’ providing a record of environmental influence at periconception constitute a valuable resource for investigating epigenetic mechanisms linking early exposures to lifelong health and disease.

Published
2022

18. Babies of South Asian and European Ancestry Show Similar Associations with Genetic Risk Score for Birth Weight Despite the Smaller Size of South Asian Newborns

Author

Suraj S. Nongmaithem, Robin N. Beaumont, Akshay Dedaniya, Andrew R. Wood, Babatunji-William Ogunkolade, Zahid Hassan, Ghattu V. Krishnaveni, Kalyanaraman Kumaran, Ramesh D. Potdar, Sirazul A. Sahariah, Murali Krishna, Chiara Di Gravio, Inder D. Mali, Alagu Sankareswaran, Akhtar Hussain, Biswajit W. Bhowmik, Abdul Kalam A. Khan, Bridget A. Knight, Timothy M. Frayling, Sarah Finer, Caroline H.D. Fall, Chittaranjan S. Yajnik, Rachel M. Freathy, Graham A. Hitman, and Giriraj R. Chandak

Subjects
Cohort Studies, Fetal Development, Asian People, Risk Factors, Endocrinology, Diabetes and Metabolism, Internal Medicine, Infant, Newborn, Birth Weight, Humans, Article
Abstract

Size at birth is known to be influenced by various fetal and maternal factors including genetic effects. South Asians have a high burden of low birthweight and cardiometabolic diseases, yet studies of common genetic variations underpinning these phenotypes are lacking. We generated independent, weighted fetal genetic score (fGS) and maternal genetic score (mGS) from 196 birthweight-associated variants identified in Europeans and conducted association analysis with various fetal birth parameters and anthropometric and cardiometabolic traits measured at different follow-up stages (5-6 years’ intervals) from seven Indian and Bangladeshi cohorts of South Asian ancestry. The results from above cohorts were compared with South Asians in UK BioBank and The Exeter Family Study of Childhood Health, a European ancestry cohort. Birthweight increased by 50.7g and 33.6g per standard deviation of fGS (p = 9.1x10-11) and mGS (p = 0.003) respectively in South Asians. A relatively weaker maternal genetic score effect compared to Europeans indicates possible different intrauterine exposures between Europeans and South Asians. Birthweight was strongly associated with body size in both childhood and adolescence (p = 3x10-5 - 1.9x10-51), however, fetal genetic score was associated with body size in childhood only (p < 0.01) and with head circumference, fasting glucose and triglycerides in adults (p < 0.01). The substantially smaller newborn size in South Asians with comparable fetal genetic effect to Europeans on birthweight suggests a significant role of factors related to fetal growth that were not captured by the present genetic scores. These factors may include different environmental exposures, maternal body size, health and nutritional status etc. Persistent influence of genetic loci on size at birth and adult metabolic syndrome in our study supports a common genetic mechanism partly explaining associations between early development and later cardiometabolic health in various populations, despite marked differences in phenotypic and environmental factors in South Asians.

Published
2022

19. DNA methylation signatures associated with cardiometabolic risk factors in children from India and The Gambia: results from the EMPHASIS study

Author

Elie, Antoun, Prachand, Issarapu, Chiara, di Gravio, Smeeta, Shrestha, Modupeh, Betts, Ayden, Saffari, Sirazul A, Sahariah, Alagu, Sankareswaran, Manisha, Arumalla, Andrew M, Prentice, Caroline H D, Fall, Matt J, Silver, Giriraj R, Chandak, Karen A, Lillycrop, and Ann, Prentice

Subjects
Male, Metabolic Syndrome, DNA methylation, Research, Early childhood risk factors, Cardiometabolic Risk Factors, India, Cardiovascular disease risk, Epigenesis, Genetic, Cohort Studies, Child, Preschool, Prevalence, Genetics, Humans, Female, Gambia, Genetic Predisposition to Disease, Epigenetics, Child, Molecular Biology, Biomarkers, EMPHASIS, Genetics (clinical), Developmental Biology
Abstract

Background The prevalence of cardiometabolic disease (CMD) is rising globally, with environmentally induced epigenetic changes suggested to play a role. Few studies have investigated epigenetic associations with CMD risk factors in children from low- and middle-income countries. We sought to identify associations between DNA methylation (DNAm) and CMD risk factors in children from India and The Gambia. Results Using the Illumina Infinium HumanMethylation 850 K Beadchip array, we interrogated DNAm in 293 Gambian (7–9 years) and 698 Indian (5–7 years) children. We identified differentially methylated CpGs (dmCpGs) associated with systolic blood pressure, fasting insulin, triglycerides and LDL-Cholesterol in the Gambian children; and with insulin sensitivity, insulinogenic index and HDL-Cholesterol in the Indian children. There was no overlap of the dmCpGs between the cohorts. Meta-analysis identified dmCpGs associated with insulin secretion and pulse pressure that were different from cohort-specific dmCpGs. Several differentially methylated regions were associated with diastolic blood pressure, insulin sensitivity and fasting glucose, but these did not overlap with the dmCpGs. We identified significant cis-methQTLs at three LDL-Cholesterol-associated dmCpGs in Gambians; however, methylation did not mediate genotype effects on the CMD outcomes. Conclusion This study identified cardiometabolic biomarkers associated with differential DNAm in Indian and Gambian children. Most associations were cohort specific, potentially reflecting environmental and ethnic differences.

Published
2022

20. Maternal vitamin B12 deficiency in rats alters DNA methylation in metabolically important genes in their offspring

Author

K. V. Shamsudheen, Subhoshree Ghose, Pujitha Kommineni, Vinay Singh Tanwar, Giriraj R. Chandak, Sridhar Sivasubbu, Sourav Ghosh, Satish Sati, Kalle Anand Kumar, Ashok Patowary, Rakesh Mishra, Vinod Scaria, Shantanu Sengupta, Lovejeet Kaur, V. Jyothi, Meghna Singh, and Manchala Raghunath

Subjects
0301 basic medicine, medicine.medical_specialty, Offspring, Clinical Biochemistry, Bisulfite sequencing, Cell Biology, General Medicine, Methylation, Epigenome, Biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, 030220 oncology & carcinogenesis, Internal medicine, DNA methylation, medicine, Vitamin B12, Methylated DNA immunoprecipitation, Molecular Biology, Mitochondrial transport
Abstract

Vitamin B12 deficiency is a critical problem worldwide and peri-conceptional deficiency of this vitamin is associated with the risk of complex cardio-metabolic diseases. Nutritional perturbations during these stages of development may lead to changes in the fetal epigenome. Using Wistar rat model system, we have earlier shown that low maternal B12 levels are associated with low birth weight, adiposity, insulin resistance, and increased triglyceride levels in the offspring, which might predispose them to the risk of cardio-metabolic diseases in adulthood. In this study, we have investigated the effects of maternal B12 deficiency on genome-wide DNA methylation profile of the offspring and the effect of rehabilitation of mothers with B12 at conception. We have performed methylated DNA immunoprecipitation sequencing of liver from pups in four groups of Wistar rats: Control (C), B12-restricted (B12R), B12-rehabilitated at conception (B12RC), and B12-rehabilitated at parturition (B12RP). We have analyzed differentially methylated signatures between the three groups as compared to controls. We have identified a total of 214 hypermethylated and 142 hypomethylated regions in the 10 kb upstream region of transcription start site in pups of B12-deficient mothers, which are enriched in genes involved in fatty acid metabolism and mitochondrial transport/metabolism. B12 rehabilitation at conception and parturition is responsible for reversal of methylation status of many of these regions to control levels suggesting a causal association with metabolic phenotypes. Thus, maternal B12 restriction alters DNA methylation of genes involved in important metabolic processes and influences the offspring phenotype, which is reversed by B12 rehabilitation of mothers at conception.

Published
2020

21. Differential expression of genes influencing mitotic processes in cord blood mononuclear cells after a pre-conceptional micronutrient-based randomized controlled trial: Pune Rural Intervention in Young Adolescents (PRIYA)

Author

Vipul Vilas Wagh, Indumathi Patta, Pooja Kunte, Deepa A. Raut, Krishna K. Sukla, Satyajeet P. Khare, K. Kumaran, Ayush Madhok, Giriraj R. Chandak, Sanjeev Galande, Utpal Tatu, Chittaranjan S. Yajnik, Dattatrey Bhat, and Caroline H.D. Fall

Subjects
Regulation of gene expression, medicine.medical_specialty, business.industry, Offspring, Organelle fission, Cell cycle, medicine.disease, Micronutrient, Insulin resistance, Endocrinology, Internal medicine, medicine, Vitamin B12, business, CLSPN
Abstract

In The Pune Maternal Nutrition Study, vitamin B12 deficiency was seen in 65% of pregnant women, folate deficiency was rare. Maternal total homocysteine concentrations were inversely associated with offspring birthweight, and low vitamin B12 and high folate concentrations predicted higher offspring adiposity and insulin resistance. These findings guided a nested pre-conceptional randomized controlled trial ‘Pune Rural Intervention in Young Adolescents (PRIYA)’. The interventions included: 1) vitamin B12+multi-micronutrients the United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP) and proteins (B12+MMN), 2) vitamin B12 (B12 alone), and 3) placebo. Intervention improved maternal pre-conceptional and in-pregnancy micronutrient nutrition. Gene expression analysis in cord blood mononuclear cells in 88 pregnancies revealed 75 differentially expressed genes between the B12+MMN and placebo groups. The enriched biological processes included G2/M phase transition, chromosome segregation, and nuclear division. Enriched pathways included, mitotic spindle checkpoint and DNA damage response while enriched human phenotypes were sloping forehead and decreased head circumference. Fructose-bisphosphatase 2 (FBP2) and Cell Division Cycle Associated 2 (CDCA2) genes were under-expressed in the B12 alone group. The latter, involved in chromosome segregation was under-expressed in both intervention groups. Based on the role of B-complex vitamins in the synthesis of nucleotides and S-Adenosyl Methionine, and the roles of vitamins A and D on gene expression, we propose that the multi-micronutrient intervention epigenetically affected cell cycle dynamics. Neonates in the B12+MMN group had the highest ponderal index. Follow up studies will reveal if the intervention and the altered biological processes influence offspring diabesity.

Published
2021

22. Sexual dimorphism in the relationship between brain complexity, volume and general intelligence (g): a cross-cohort study

Author

Anca-Larisa Sandu, Gordon D. Waiter, Roger T. Staff, Nafeesa Nazlee, Tina Habota, Chris J. McNeil, Dorota Chapko, Justin H. Williams, Caroline H. D. Fall, Giriraj R. Chandak, Shailesh Pene, Murali Krishna, Andrew M. McIntosh, Heather C. Whalley, Kalyanaraman Kumaran, Ghattu V. Krishnaveni, and Alison D. Murray

Subjects
Cohort Studies, Male, Sex Characteristics, Multidisciplinary, Intelligence, Brain, Humans, Brain/pathology, Female, Child, Magnetic Resonance Imaging, Magnetic Resonance Imaging/methods
Abstract

Changes in brain morphology have been reported during development, ageing and in relation to different pathologies. Brain morphology described by the shape complexity of gyri and sulci can be captured and quantified using fractal dimension (FD). This measure of brain structural complexity, as well as brain volume, are associated with intelligence, but less is known about the sexual dimorphism of these relationships. In this paper, sex differences in the relationship between brain structural complexity and general intelligence (g) in two diverse geographic and cultural populations (UK and Indian) are investigated. 3D T1-weighted magnetic resonance imaging (MRI) data and a battery of cognitive tests were acquired from participants belonging to three different cohorts: Mysore Parthenon Cohort (MPC); Aberdeen Children of the 1950s (ACONF) and UK Biobank. We computed MRI derived structural brain complexity and g estimated from a battery of cognitive tests for each group. Brain complexity and volume were both positively corelated with intelligence, with the correlations being significant in women but not always in men. This relationship is seen across populations of differing ages and geographical locations and improves understanding of neurobiological sex-differences.

Published
2021

23. FUT Genotypes, Secretor Status, H.pylori Antibody Levels and Vitamin-B12 Concentrations in Indians

Author

Pooja Kunte, Giriraj R. Chandak, Chittaranjan S. Yajnik, Rajashree Kamat, Dattatray S. Bhat, Anand Chaphekar, Akshay Dedaniya, Deepa A. Raut, and Krishna Kishore Sukla

Subjects
Body fluid, Blood type, Saliva, Nutrition and Dietetics, biology, Medicine (miscellaneous), Helicobacter pylori, biology.organism_classification, fluids and secretions, Antigen, ABO blood group system, Nutrient-Gene Interactions, Genotype, Immunology, biology.protein, Antibody, Food Science
Abstract

OBJECTIVES: Background: The FUT2 gene is responsible for the secretion of ABO blood type antigens into the body fluids (saliva, mucous, urine, tears, breast milk, sweat, and semen). Those who secrete the antigens into body fluids are call secretors, those who do not are called non-secretors. Hypothesis: GWAS studies have reported FUT gene variants to be associated with circulating vitamin-B12 (Vit-B12) concentrations. Missense mutations in the FUT2 gene result in a non-secretor phenotype. Thus, the secretory status of an individual may affect circulating vitamin-B12 concentrations over and above the genotype. METHODS: Materials and Methods: We included 780 participants (271 children, 282 mothers, and 227 fathers) from Pune Maternal Nutrition Study (PMNS). We measured the secretor status of individuals in saliva by hemagglutination test. A total of eight genetic variants including six SNPs from the FUT2 gene (rs492602, rs681343, rs281377, rs601338, rs1800027, and rs602662) and two SNPs from the FUT6 gene (rs3760776 and rs3760775) from our previous GWAS study were correlated with circulating vitamin-B12 levels. We tested the associations of FUT gene variants with secretor status phenotype and of the secretor phenotype with circulating vit-B12, folate, and ferritin concentrations in addition to H.pylori antibody levels. RESULTS: Results and Discussion: We found 33% of participants were non-secretors compared to 20% reported in Western Caucasian populations. Non-secretors had higher vitamin-B12 concentrations but not of folate and ferritin, vitamin-B12 associations were over and above FUT genotypes. Non-secretors showed a higher response to Vit-B12 supplementation. We found a FUT2 haplotype () to be strongly associated with Vit-B12 concentrations and non-secretor status. Non-secretors had lower H.pylori antibody concentrations. FUT6 genotype and haplotype were associated with Vit-B12 concentrations but not with secretor status and H.pylori antibody levels. CONCLUSIONS: Our data suggest that secretor status may influence Vit-B12 concentrations through susceptibility to H.pylori infection and possibly other gut microbiota. A higher frequency of non-secretors in Indians could offer a selective advantage against Vit-B12 deficiency. FUNDING SOURCES: BBSRC, UK; MRC, UK; WELLCOME TRUST, UK; DBT, India; ICMR India

Published
2021

24. Associations of genetic scores for birth weight with newborn size and later Anthropometric traits and cardiometabolic risk markers in South Asians

Author

Suraj S Nongmaithem, Robin N Beaumont, Akshay Dedaniya, Andrew R Wood, Babatunji-William Ogunkolade, Zahid Hassan, Ghattu V Krishnaveni, Kalyanaraman Kumaran, Ramesh D Potdar, Sirajul A Sahariah, Murali Krishna, Chiara Di Gravio, Inder D Mali, Alagu Sankareswaran, Akhtar Hussain, Biswajit W Bhowmik, Abdul Kalam A Khan, Bridget A Knight, Timothy M Frayling, Sarah Finer, Caroline HD Fall, Chittaranjan S Yajnik, Rachel M Freathy, Graham A Hitman, and Giriraj R Chandak

Abstract

We recently reported genetic variants associated with birth weight and their effect on future cardiometabolic risk in Europeans. Despite a higher burden of low birth weight and cardiometabolic disorders, such studies are lacking in South Asians. We generated fetal and maternal genetic scores (fGS and mGS) from 196 birth weight-associated variants identified in Europeans and conducted association analysis with various birth measures and serially measured anthropometric and cardiometabolic traits from seven Indian and Bangladeshi cohorts. Although fGS and mGS were comparable to Europeans, birth weight was substantially smaller suggesting strong environmental constraints on fetal growth in South Asians. Birth weight increased by 50.7g and 33.6g per standard deviation fGS (P=9.1×10−11) and mGS (P=0.003) in South Asians. The fGS was further associated with childhood body size and head circumference, fasting glucose, and triglycerides in adults (P

Published
2021

25. Author response: Insights from a Pan India Sero-Epidemiological survey (Phenome-India Cohort) for SARS-CoV2

Author

Mrigank Srivastava, Subramanian Venkatesan, Vipin Hallan, Shabda E Kulsange, Raju Khan, Rekha Chouhan, Narendra Vijay Tripude, Sakshi Vashisht, Rahul Chakraborty, Jatin Kalita, Selvamani Raja Vijayakumar, Jasleen Kaur, Susanta Kar, R.V.K. Singh, Abujunaid Habib Khan, Sundaram Acharya, Shrikant R. Mulay, Dayanidhi Singh, Nitika Kapoor, Pinreddy Karunakar, Sachin N Mahajan, Rohit Yadav, Anjali Srivastava, Prakash M. Halami, Anirban Pal, Anamika Kothari, Bhawana Tomar, Babita Sharma, Anil Ku Maurya, Mahesh J. Kulkarni, Akash Pratap Singh, Arvindkumar H Chaurasiya, Shantanu Sengupta, Saumya Ray Chaudhury, Partha Chakrabarti, Viren Sardana, Anas Saifi, Prasenjit Manna, Aiswarya R Nair, Mahesh S. Dharne, Ravindra P Veeranna, Tridip Phukan, Muthukumar Serva Peddha, Amita P Patil, Birendra Singh Rawat, Gopinath M Sundaram, Mayuri Bhadange, Shweta Verma, Umakanta Subudhi, Vijay Lakshmi Jamwal, Vasudev Wagh, Firdaus Fatima, Ganesh Venkatachalam, Debashish Ghosh, Avinash Mishra, Manikandan Subramanian, Rintu Kutum, Rajesh P. Ringe, Sumit G. Gandhi, Purbasha Bhattacharya, Devendra Singh Parihar, Shilpa Paranjape, Dipyaman Ganguly, Yennapu Madhavi, Shalini Pradhan, Yogendra Padwad, Parimala Karuppanan, Sarita Thakran, Ved Varun Aggarwal, Pawan Gupta, Piyush Singh Jamwal, Pankaj Bharali, Satyartha Prakash, Amit Tuli, Jit Sarkar, Samir Damare, Ajay Agarwal, Rakeshkumar Yadav, Balthu Narender Kumar, Anoop Puthiyamadam, Giriraj R. Chandak, Murugan Veerapandian, Debasis Dash, Ajinkya Khilari, Sumit Dahiya, Mahesh Anumalla, Sharmistha Sarkar, Kalpana Chodankar, Anupama Thakur, Ghanshyam Thakkar, Narahari G Sastry, Iranna Gogeri, Deepak Sharma, Surabhi Seth, Pradip Sen, Harish Kumar Sardana, Vinay Kumar Agarwal, Wahengbam Romi, Rashmi Kumar, Adarsh Velayudhanpillai, Nitin Bhatheja, Ashok Kumar Raman, Praveen Singh, Virendra Kumar, Sunanda Singhmar, Dinesh Gupta, Shaziya Khan, Damanpreet Singh, Madhav Nilakanth Mugale, Rajat Ujjainiya, Karthik Bharadwaj Tallapaka, Elapavalooru V.S.S.K. Babu, Kiran A Kumar, Rakesh Joshi, Rajeev K. Sukumaran, Amarnarayan D, Sujay Krishna Maity, Dhansekaran Shanmugam, Akanksha Sharma, Akash Kumar Bhaskar, Krishna Khairnar, Gaura Chaturvedi, Amit Lahiri, Vikram Patial, Suresh Kumar Anandasadagopan, Prajeesh Kooloth Valappil, Drishti Soni, Rishabh Jain, Sistla Ramakrishna, Dibyajyoti Ozah, Salwa Naushin, Ravi Kumar Sahu, Geethavani Rayasam, Anurag Agrawal, Sayed G Dastager, and Vandana Singh

Subjects
medicine.medical_specialty, business.industry, Environmental health, Cohort, Epidemiology, Medicine, Phenome, business
Published
2021

26. Insights from a Pan India Sero-Epidemiological survey (Phenome-India Cohort) for SARS-CoV2

Author

Rajeev K. Sukumaran, Amarnarayan D, Sujay Krishna Maity, Ravindra P Veeranna, Ganesh Venkatachalam, Dayanidhi Singh, Pinreddy Karunakar, Sundaram Acharya, Pawan Gupta, Narendra Vijay Tirpude, Anoop Puthiyamadam, Giriraj R. Chandak, Nitika Kapoor, Babita Sharma, Mahesh Anumalla, Ajinkya Khilari, Dipyaman Ganguly, Prakash M. Halami, Partha Chakrabarti, Birendra Singh Rawat, Gopinath M Sundaram, Shweta Verma, Rakeshkumar Yadav, Purbasha Bhattacharya, Rintu Kutum, Surabhi Seth, Shilpa Paranjape, Sharmistha Sarkar, Viren Sardana, Sunanda Singhmar, Kalpana Chodankar, Mayuri Bhadange, Ajay Agarwal, Ghanshyam Thakkar, Suresh Kumar Anandasadagopan, Debasis Dash, A. Kiran Kumar, Praveen Singh, Debashish Ghosh, Rekha Chouhan, Rajesh P. Ringe, Drishti Soni, Sumit Dahiya, Rohit Yadav, Deepak Sharma, Jasleen Kaur, Yennapu Madhavi, Dibyajyoti Ozah, Satyartha Prakash, Amit Tuli, Syed G. Dastager, Pradip Sen, Arvindkumar H Chaurasiya, Yogendra Padwad, Vipin Hallan, Jit Sarkar, Akanksha Sharma, Samir Damare, Parimala Karuppanan, Anjali Srivastava, Piyush Singh Jamwal, Pankaj Bharali, Tridip Phukan, Amit Lahiri, Bhawna Tomar, Muthukumar Serva Peddha, Amita P Patil, Selvamani Raja Vijayakumar, Salwa Naushin, Sachin N Mahajan, Mahesh J. Kulkarni, Damanpreet Singh, Anil Ku Maurya, Shabda E Kulsange, Virendra Kumar, Akash Kumar Bhaskar, Ravi Kumar Sahu, Krishna Khairnar, Geethavani Rayasam, Prajeesh Kooloth-Valappil, Rashmi Kumar, Madhav Nilakanth Mugale, Shrikant R. Mulay, Susanta Kar, Balthu Narender Kumar, Umakanta Subudhi, Aiswarya R Nair, Anurag Agrawal, Gaura Chaturvedi, Vikram Patial, Sumit G. Gandhi, Abu Junaid Khan, Adarsh Velayudhanpillai, Anupma Thakur, Anirban Pal, Anamika Kothari, Devendra Singh Parihar, Sarita Thakran, Shantanu Sengupta, Shakshi Vashisht, Nitin Bhatheja, Vasudev Wagh, Firdaus Fatima, Prasenjit Manna, Ashok Kumar Raman, Mahesh S. Dharne, Vijay Lakshmi Jamwal, Vandana Singh, Murugan Veerapandian, G. Narahari Sastry, Manikandan Subramanian, Ran Vijay Kumar Singh, Iranna Gogeri, Harish Kumar Sardana, Mrigank Srivastava, Subramanian Venkatesan, Raju Khan, Dhanasekaran Shanmugam, Rahul Chakraborty, Jatin Kalita, Anas Saifi, Sistla Ramakrishna, Rishabh Jain, Saumya Ray Chaudhury, Shaziya Khan, Rajat Ujjainiya, Karthik Bharadwaj Tallapaka, Elapavalooru V.S.S.K. Babu, Avinash Mishra, Wahengbam Romi, Shalini Pradhan, Ved Varun Aggarwal, Dinesh Gupta, Vinay Kumar Agarwal, Akash Pratap Singh, and Rakesh Joshi

Subjects
Male, Time Factors, 030204 cardiovascular system & hematology, Antibodies, Viral, Serology, 0302 clinical medicine, Risk Factors, Seroepidemiologic Studies, Pandemic, Epidemiology, 030212 general & internal medicine, Longitudinal Studies, Biology (General), General Neuroscience, neutralizing antibody, General Medicine, Universal precautions, Cohort, Host-Pathogen Interactions, Medicine, Female, medicine.medical_specialty, 2019-20 coronavirus outbreak, QH301-705.5, Science, India, Lower risk, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, Odds, COVID-19 Serological Testing, 03 medical and health sciences, Predictive Value of Tests, Environmental health, medicine, Humans, Medical history, General Immunology and Microbiology, business.industry, SARS-CoV-2, antibody stability, Industrial research, COVID-19, Odds ratio, Antibodies, Neutralizing, Confidence interval, Immunity, Humoral, sero-prevalence, SARS-CoV2, business, Biomarkers, Demography
Abstract

Background: India has been amongst the most affected nations during the SARS CoV2 pandemic, with sparse data on country wide spread of asymptomatic infections and antibody persistence. This longitudinal cohort study was aimed to evaluate SARS CoV2 seropositivity rate as a marker of infection and evaluate temporal persistence of antibodies with neutralization capability and to infer possible risk factors for infection. Methods: Council of Scientific and Industrial Research, India (CSIR) with its more than 40 laboratories and centers in urban and semi urban settings spread across the country piloted the pan country surveillance. 10427 adult individuals working in CSIR laboratories and their family members based on voluntary participation were assessed for antibody presence and stability was analyzed over 6 months utilizing qualitative Elecysys SARS CoV2 specific antibody kit and GENScript cPass SARS CoV2 Neutralization Antibody Detection Kit. Along with demographic information, possible risk factors were evaluated through self to be filled online forms with data acquired on blood group type, occupation type, addiction and habits including smoking and alcohol, diet preferences, medical history and transport type utilized. Symptom history and information on possible contact and compliance with COVID 19 universal precautions was also obtained. Findings:1058 individuals (10.14%) had antibodies against SARS CoV2. A follow up on 346 seropositive individuals after three months revealed stable to higher antibody levels against SARS CoV2 but declining plasma activity for neutralizing SARS CoV2 receptor binding domain and ACE2 interaction. A repeat sampling of 35 individuals, at six months, revealed declining antibody levels while the neutralizing activity remained stable compared to three months. Majority of seropositive individuals (75%) did not recall even one of nine symptoms since March 2020. Fever was the most common symptom with one fourth reporting loss of taste or smell. Significantly associated risks for seropositivity (Odds Ratio, 95% CI, p value) were observed with usage of public transport (1.79, 1.43 to 2∙24, 2.81561x10-6), occupational responsibilities such as security, housekeeping personnel etc. (2.23, 1.92 to 2.59, 6.43969x10-26), non smokers (1.52, 1.16 to 1.99, 0.02) and non vegetarianism (1.67, 1.41 to 1.99, 3.03821x10-8). An iterative regression analysis was confirmatory and led to only modest changes to estimates. Predilections for seropositivity was noted with specific ABO blood groups; O was associated with a lower risk. Interpretation: In a first of its kind study from India, we report the seropositivity in a country wide cohort and identify variable susceptible associations for contacting infection. Serology and Neutralizing Antibody response provides much sought for general insights on the immune response to the virus among Indians and will be an important resource for designing vaccination strategies. Funding: Council of Scientific and Industrial Research, India (CSIR)

Published
2021

27. Rapid and accurate nucleobase detection using FnCas9 and its application in COVID-19 diagnosis

Author

Souvik Maiti, Sunaina Singh, Harsha Lad, Manoj Kumar, Pradeep Kumar Patra, Riya Rauthan, Paras Sehgal, Sundaram Acharya, Dipanjali Sinha, Saumya Sharma, Rhythm Phutela, Poorti Kathpalia, Deepanjan Paul, Sajal Sarkar, Giriraj R. Chandak, Bala Pesala, Govind K. Makharia, Sneha Gulati, Khushboo Singhal, Namrata Sharma, Gyan Ranjan, Mohd Azhar, Rahul C. Bhoyar, Meghali Aich, Debojyoti Chakraborty, and Asgar Hussain Ansari

Subjects
Coronavirus disease 2019 (COVID-19), CoV2, Computer science, Biomedical Engineering, Biophysics, 02 engineering and technology, Computational biology, Biosensing Techniques, Smartphone application, 01 natural sciences, Rapid detection, Sensitivity and Specificity, Article, Nucleobase, Clinical prognosis, COVID-19 Testing, SNV detection, Electrochemistry, Humans, Detection theory, Cas9, SARS-CoV-2, 010401 analytical chemistry, COVID-19, General Medicine, 021001 nanoscience & nanotechnology, FnCas9, 0104 chemical sciences, FELUDA, RNA, Viral, LFA, 0210 nano-technology, Limited resources, Biotechnology, CRISPRDx
Abstract

Rapid detection of DNA/RNA pathogenic sequences or variants through point-of-care diagnostics is valuable for accelerated clinical prognosis, as witnessed during the recent COVID-19 outbreak. Traditional methods relying on qPCR or sequencing are tough to implement with limited resources, necessitating the development of accurate and robust alternative strategies. Here, we report FnCas9 Editor Linked Uniform Detection Assay (FELUDA) that utilizes a direct Cas9 based enzymatic readout for detecting nucleobase and nucleotide sequences without trans-cleavage of reporter molecules. We also demonstrate that FELUDA is 100% accurate in detecting single nucleotide variants (SNVs), including heterozygous carriers, and present a simple web-tool JATAYU to aid end-users. FELUDA is semi-quantitative, can adapt to multiple signal detection platforms, and deploy for versatile applications such as molecular diagnosis during infectious disease outbreaks like COVID-19. Employing a lateral flow readout, FELUDA shows 100% sensitivity and 97% specificity across all ranges of viral loads in clinical samples within 1hr. In combination with RT-RPA and a smartphone application True Outcome Predicted via Strip Evaluation (TOPSE), we present a prototype for FELUDA for CoV-2 detection closer to home.

Published
2021

28. The REVAMP study: research exploring various aspects and mechanisms in preeclampsia: study protocol

Author

Girija Wagh, Nisha S. Wadhwani, Arun Kinare, Giriraj R. Chandak, Priscilla Joshi, Sanjay Gupte, Savita Mehendale, Narayanan Subramaniam Mani, Sanjay Lalwani, Deepali P. Sundrani, Manish M. Tipnis, Caroline H.D. Fall, Sadhana Joshi, and Nomita Chandhiok

Subjects
medicine.medical_specialty, Placenta, Reproductive medicine, India, Long chain polyunsaturated fatty acids, Risk Assessment, lcsh:Gynecology and obstetrics, Preeclampsia, Developmental programming, 03 medical and health sciences, Study Protocol, 0302 clinical medicine, Dietary Fats, Unsaturated, Pre-Eclampsia, Pregnancy, Risk Factors, medicine, Humans, 030212 general & internal medicine, Longitudinal Studies, Prospective Studies, Family history, Socioeconomic status, reproductive and urinary physiology, lcsh:RG1-991, 030219 obstetrics & reproductive medicine, Obstetrics, business.industry, Infant, Newborn, Obstetrics and Gynecology, Infant, Prenatal Care, Anthropometry, medicine.disease, Fetal Blood, Research Design, Case-Control Studies, Cohort, Etiology, Gestation, Female, Pregnancy Trimesters, business
Abstract

Background Preeclampsia is a major cause of maternal, fetal and neonatal morbidity and mortality, particularly in developing countries. Considering the burden of preeclampsia and its associated complications, it is important to understand the underlying risk factors and mechanisms involved in its etiology. There is considerable interest in the potential for dietary long chain polyunsaturated fatty acids (LCPUFA) as a therapeutic intervention to prevent preeclampsia, as they are involved in angiogenesis, oxidative stress, and inflammatory pathways. Methods The REVAMP study (Research Exploring Various Aspects and Mechanisms in Preeclampsia) follows a cohort of pregnant women from early pregnancy until delivery to examine longitudinally the associations of maternal LCPUFA with clinical outcome in preeclampsia. A multisite centre for advanced research was established and pregnant women coming to Bharati hospital and Gupte hospital, Pune, India for their first antenatal visit are recruited and followed up at 11–14 weeks, 18–22 weeks, 26–28 weeks, and at delivery. Their personal, obstetric, clinical, and family history are recorded. Anthropometric measures (height, weight), food frequency questionnaire (FFQ), physical activity, socioeconomic status, fetal ultrasonography, and color Doppler measures are recorded at different time points across gestation. Maternal blood at all time points, cord blood, and placenta at delivery are collected, processed and stored at − 80 °C. The children’s anthropometry is assessed serially up to the age of 2 years, when their neurodevelopmental scores will be assessed. Discussion This study will help in early identification of pregnant women who are at risk of developing preeclampsia. The prospective design of the study for the first time will establish the role of LCPUFA in understanding the underlying biochemical and molecular mechanisms involved in preeclampsia and their association with developmental programming in children.

Published
2019

29. Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis

Author

András Szabó, Prachand Issarapu, Emmanuelle Masson, Peter Bugert, Denise Lasher, Sumit Paliwal, Claudia Ruffert, Shin Hamada, K. Radha Mani, Helmut Laumen, Jian-Min Chen, Atsushi Masamune, David A. Groneberg, Katharina Seltsam, Kiyoshi Kume, Xunjun Xiao, Maren Ewers, Eriko Nakano, M. Michael Barmada, Tooru Shimosegawa, Jonas Rosendahl, Giriraj R. Chandak, Thomas Müller, Mark E. Lowe, Miklós Sahin-Tóth, Heiko Witt, Seema Bhaskar, David C. Whitcomb, and Claude Férec

Subjects
Adult, Male, medicine.medical_specialty, Time Factors, Adolescent, medicine.medical_treatment, DNA Mutational Analysis, medicine.disease_cause, Article, Pathogenesis, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Pancreatitis, Chronic, Internal medicine, medicine, Humans, Pancreatic lipase, Genetic Predisposition to Disease, Child, Gene, Early onset, Mutation, Protease, Virulence, Hepatology, biology, business.industry, Infant, Newborn, Gastroenterology, Infant, DNA, Lipase, medicine.disease, Trypsin, Endocrinology, Child, Preschool, 030220 oncology & carcinogenesis, biology.protein, Pancreatitis, Female, 030211 gastroenterology & hepatology, business, Biomarkers, Follow-Up Studies, Peptide Hydrolases, medicine.drug
Abstract

OBJECTIVES. Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intra-pancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase (CEL) emerged as a trypsin-independent risk gene. Here, we evaluated PNLIP encoding pancreatic lipase as a potential novel susceptibility gene for CP. METHODS. We analyzed all 13 PNLIP exons in 429 German non-alcoholic CP patients and in 600 German control subjects, in 632 patients and 957 controls from France, and in 223 patients and 1070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 CP patients and 1849 controls originating from Germany, USA and India. We assessed the cellular secretion, lipase activity and proteolytic stability of recombinant PNLIP variants. RESULTS. In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P=0.02, OR=5.7, 95% CI=1.1–38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) versus controls (1/957 [0.1%]) (P=0.04, OR=7.6, 95% CI=0.9–172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1163 cases (1.1%) and in 3/3000 controls (0.1%) (OR=11.3, 95% CI=3.0–49.9, P

Published
2019

30. Associations of genetic scores for birth weight with newborn size and later anthropometric traits and cardiometabolic risk markers in South Asians

Author

Rachel M. Freathy, Akhtar Hussain, Ghattu V. Krishnaveni, Akshay Dedaniya, Alagu Sankareswaran, B W Ogunkolade, Murali Krishna, Bridget A. Knight, Graham A. Hitman, Giriraj R. Chandak, Robin N Beaumont, Sirajul A Sahariah, Ramesh D. Potdar, Kalyanaraman Kumaran, Abdul Kalam A Khan, Chiara Di Gravio, Andrew R. Wood, Sarah Finer, Zahid Hassan, Biswajit W Bhowmik, Suraj S. Nongmaithem, Timothy M. Frayling, Chittaranjan S. Yajnik, Inder D Mali, and Caroline H.D. Fall

Subjects
Cardiometabolic risk, Fasting glucose, Fetus, Low birth weight, South asia, business.industry, Birth weight, Medicine, Anthropometry, medicine.symptom, business, Demography, Genetic association
Abstract

We recently reported genetic variants associated with birth weight and their effect on future cardiometabolic risk in Europeans. Despite a higher burden of low birth weight and cardiometabolic disorders, such studies are lacking in South Asians. We generated fetal and maternal genetic scores (fGS and mGS) from 196 birth weight-associated variants identified in Europeans and conducted association analysis with various birth measures and serially measured anthropometric and cardiometabolic traits from seven Indian and Bangladeshi cohorts. Although fGS and mGS were comparable to Europeans, birth weight was substantially smaller suggesting strong environmental constraints on fetal growth in South Asians. Birth weight increased by 50.7g and 33.6g per standard deviation fGS (P=9.1x10-11) and mGS (P=0.003) in South Asians. The fGS was further associated with childhood body size and head circumference, fasting glucose, and triglycerides in adults (P

Published
2021

31. Protocol for a cluster randomised trial evaluating a multifaceted intervention starting preconceptionally—Early Interventions to Support Trajectories for Healthy Life in India (EINSTEIN): a Healthy Life Trajectories Initiative (HeLTI) Study

Author

Pablo A. Nepomnaschy, Jacquetta M. Trasler, Patrick O. McGowan, Ramaswamy Balasubramaniam, Saumyadipta Pyne, Stephen G. Matthews, K.S. Joseph, Janis Baird, Nalini Singhal, Marie-Claude Martin, Antonisamy Belavendra, Geoffrey L. Hammond, Sandra T. Davidge, Manohar Prabhu Prasad, Nusrat Husain, Prabhat Jha, Kumar Gavali Suryanarayana, Stephen J. Lye, Cindy-Lee Dennis, Kalyanaraman Kumaran, Giriraj R. Chandak, Daniel W. Sellen, Vivek Padvetnaya, Harshpal Singh Sachdev, Mary Barker, Robert H. J. Bandsma, Sadhana Joshi, Stephanie A. Atkinson, Zulfiqar A Bhutta, Kang Lee, Murali Krishna, Ghattu V. Krishnaveni, Prakesh S. Shah, Sirazul A. Sahariah, Caroline H.D. Fall, Chittaranjan S. Yajnik, and Elena M. Comelli

Subjects
Adult, Rural Population, medicine.medical_specialty, Epidemiology, Psychological intervention, India, Mothers, Nutritional Status, Environmental pollution, preventive medicine, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Intervention (counseling), medicine, Humans, 030212 general & internal medicine, Child, Preventive healthcare, Randomized Controlled Trials as Topic, Community Health Workers, business.industry, Public health, public health, Infant, General Medicine, Middle Aged, 3. Good health, Local community, Family medicine, Child, Preschool, Medicine, Female, business, Breast feeding, 030217 neurology & neurosurgery
Abstract

IntroductionThe Healthy Life Trajectories Initiative is an international consortium comprising four harmonised but independently powered trials to evaluate whether an integrated intervention starting preconceptionally will reduce non-communicable disease risk in their children. This paper describes the protocol of the India study.Methods and analysisThe study set in rural Mysore will recruit ~6000 married women over the age of 18 years. The village-based cluster randomised design has three arms (preconception, pregnancy and control; 35 villages per arm). The longitudinal multifaceted intervention package will be delivered by community health workers and comprise: (1) measures to optimise nutrition; (2) a group parenting programme integrated with cognitive–behavioral therapy; (3) a lifestyle behaviour change intervention to support women to achieve a diverse diet, exclusive breast feeding for the first 6 months, timely introduction of diverse and nutritious infant weaning foods, and adopt appropriate hygiene measures; and (4) the reduction of environmental pollution focusing on indoor air pollution and toxin avoidance.The primary outcome is adiposity in children at age 5 years, measured by fat mass index. We will report on a host of intermediate and process outcomes. We will collect a range of biospecimens including blood, urine, stool and saliva from the mothers, as well as umbilical cord blood, placenta and specimens from the offspring.An intention-to-treat analysis will be adopted to assess the effect of interventions on outcomes. We will also undertake process and economic evaluations to determine scalability and public health translation.Ethics and disseminationThe study has been approved by the institutional ethics committee of the lead institute. Findings will be published in peer-reviewed journals. We will interact with policy makers at local, national and international agencies to enable translation. We will also share the findings with the participants and local community through community meetings, newsletters and local radio.Trial registration numberISRCTN20161479, CTRI/2020/12/030134; Pre-results.

Published
2021

32. Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author

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

Subjects
0303 health sciences, Transferability, Translation (biology), Type 2 diabetes, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Global health, medicine, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Published
2020

33. Rapid, accurate, nucleobase detection using FnCas9

Author

Mohd Azhar, Sundaram Acharya, Khushboo Singhal, Souvik Maiti, Govind K. Makharia, Paras Sehgal, Namrata Sharma, Harsha Lad, Dipanjali Sinha, Giriraj R. Chandak, Poorti Kathpalia, Rhythm Phutela, Bala Pesala, Asgar Hussain Ansari, Meghali Aich, Pradeep Kumar Patra, Suchita Singh, Gyan Ranjan, Sachin Sharma, Rahul C. Bhoyar, Manoj Kumar, Deepanjan Paul, Riya Rauthan, Sneha Gulati, and Debojyoti Chakraborty

Subjects
Cas9, Computer science, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Nucleic acid sequence, Single sentence, Detection theory, Computational biology, Rapid detection, Limited resources, Nucleobase
Abstract

Rapid detection of pathogenic sequences or variants in DNA and RNA through a point-of-care diagnostic approach is valuable for accelerated clinical prognosis as has been witnessed during the recent COVID-19 outbreak. Traditional methods relying on qPCR or sequencing are difficult to implement in settings with limited resources necessitating the development of accurate alternative testing strategies that perform robustly. Here, we present FnCas9 Editor Linked Uniform Detection Assay (FELUDA) that employs a direct Cas9 based enzymatic readout for detecting nucleotide sequences and identifying nucleobase identity without the requirement of trans-cleavage activity of reporter molecules. We demonstrate that FELUDA is 100% accurate in detecting single nucleotide variants (SNVs) including heterozygous carriers of a mutation and present a simple design strategy in the form of a web-tool, JATAYU, for its implementation. FELUDA is semi quantitative, can be adapted to multiple signal detection platforms and can be quickly designed and deployed for versatile applications such as infectious disease outbreaks like COVID-19. Using a lateral flow readout within 1h, FELUDA shows 100% sensitivity and 97% specificity across all range of viral loads in clinical samples. In combination with RT-RPA and a smartphone application True Outcome Predicted via Strip Evaluation (TOPSE), we present a prototype for FELUDA for CoV-2 detection at home.Single sentence summaryA method to identify nucleotide sequence or nucleobase identity using FnCas9 and its implementation in the rapid and accurate diagnosis of SARS-CoV-2

Published
2020

34. Periconceptional environment predicts leukocyte telomere length in a cross-sectional study of 7-9 year old rural Gambian children

Author

Jessica L. Buxton, Matt J. Silver, Kim Maasen, Modupeh Betts, Caroline H.D. Fall, Andrew M. Prentice, Sophie E. Moore, Philip T. James, Giriraj R. Chandak, Interne Geneeskunde, and RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome

Subjects
0301 basic medicine, Male, Molecular composition, Cross-sectional study, Epidemiology, Intrauterine growth restriction, lcsh:Medicine, dna methylation, one-carbon metabolites, 0302 clinical medicine, Genetics research, Leukocytes, Medicine, oxidative stress, Child, lcsh:Science, Telomere Shortening, Multidisciplinary, seasonality, Confounding, Regression analysis, Telomere, Early life, Child, Preschool, Regression Analysis, Female, Gambia, Seasons, intrauterine growth restriction, Offspring, BIRTH, 030209 endocrinology & metabolism, Paediatric research, folate, Article, 03 medical and health sciences, Medical research, Developmental biology, Humans, business.industry, MORTALITY, lcsh:R, association, medicine.disease, Ageing, 030104 developmental biology, Cross-Sectional Studies, exposure, Fertilization, lcsh:Q, business, biological, Demography
Abstract

Early life exposures are important predictors of adult disease risk. Although the underlying mechanisms are largely unknown, telomere maintenance may be involved. This study investigated the relationship between seasonal differences in parental exposures at time of conception and leukocyte telomere length (LTL) in their offspring. LTL was measured in two cohorts of children aged 2 yrs (N = 487) and 7–9 yrs (N = 218). The association between date of conception and LTL was examined using Fourier regression models, adjusted for age, sex, leukocyte cell composition, and other potential confounders. We observed an effect of season in the older children in all models [likelihood ratio test (LRT) χ²2 = 7.1, p = 0.03; fully adjusted model]. LTL was greatest in children conceived in September (in the rainy season), and smallest in those conceived in March (in the dry season), with an effect size (LTL peak–nadir) of 0.60 z-scores. No effect of season was evident in the younger children (LRT χ²2 = 0.87, p = 0.65). The different results obtained for the two cohorts may reflect a delayed effect of season of conception on postnatal telomere maintenance. Alternatively, they may be explained by unmeasured differences in early life exposures, or the increased telomere attrition rate during infancy.

Published
2020

35. Type 1 diabetes genetic risk score is discriminative of diabetes in non-Europeans: evidence from a study in India

Author

Seema Bhaskar, Kashyap A. Patel, Chittaranjan S. Yajnik, Michael N. Weedon, Seth A. Sharp, Kalpana S. Jog, Richard A. Oram, James W. Harrison, Giriraj R. Chandak, Divya Sri Priyanka Tallapragada, and Alma Baptist

Subjects
Male, 0301 basic medicine, endocrine system diseases, lcsh:Medicine, Type 2 diabetes, 0302 clinical medicine, Discriminative model, immune system diseases, Genetics research, Medicine, Young adult, lcsh:Science, Child, education.field_of_study, Multidisciplinary, Molecular medicine, Middle Aged, Type 1 diabetes, Female, Adult, endocrine system, Adolescent, Population, India, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Asian People, Diabetes mellitus, Humans, SNP, Genetic Predisposition to Disease, education, Alleles, business.industry, lcsh:R, fungi, nutritional and metabolic diseases, medicine.disease, Diabetes Mellitus, Type 1, 030104 developmental biology, Risk factors, Diabetes Mellitus, Type 2, Case-Control Studies, lcsh:Q, business, Demography
Abstract

Type 1 diabetes (T1D) is a significant problem in Indians and misclassification of T1D and type 2 diabetes (T2D) is a particular problem in young adults in this population due to the high prevalence of early onset T2D at lower BMI. We have previously shown a genetic risk score (GRS) can be used to discriminate T1D from T2D in Europeans. We aimed to test the ability of a T1D GRS to discriminate T1D from T2D and controls in Indians. We studied subjects from Pune, India of Indo-European ancestry; T1D (n = 262 clinically defined, 200 autoantibody positive), T2D (n = 345) and controls (n = 324). We used the 9 SNP T1D GRS generated in Europeans and assessed its ability to discriminate T1D from T2D and controls in Indians. We compared Indians with Europeans from the Wellcome Trust Case Control Consortium study; T1D (n = 1963), T2D (n = 1924) and controls (n = 2938). The T1D GRS was discriminative of T1D from T2D in Indians but slightly less than in Europeans (ROC AUC 0.84 v 0.87, p

Published
2020

36. Rapid, field-deployable nucleobase detection and identification using FnCas9

Author

Souvik Maiti, Meghali Aich, Mohd Azhar, Govind K. Makharia, Khushboo Singhal, Dipanjali Sinha, Harsha Lad, Manoj Kumar, Debojyoti Chakraborty, Giriraj R. Chandak, Saumya Sharma, Pradeep Kumar Patra, Rhythm Phutela, Namrata Sharma, and Asgar Hussain Ansari

Subjects
Clinical prognosis, Coronavirus disease 2019 (COVID-19), Computer science, Nucleic acid, CRISPR, Detection theory, Computational biology, Nucleobase
Abstract

Detection of pathogenic sequences or variants in DNA and RNA through a point-of-care diagnostic approach is valuable for rapid clinical prognosis. In recent times, CRISPR based detection of nucleic acids has provided an economical and quicker alternative to sequencing-based platforms which are often difficult to implement in the field. Here, we present FnCas9 Editor Linked Uniform Detection Assay (FELUDA) that employs a highly accurate enzymatic readout for detecting nucleotide sequences, identifying nucleobase identity and inferring zygosity with precision. We demonstrate that FELUDA output can be adapted to multiple signal detection platforms and can be quickly designed and deployed for versatile applications including rapid diagnosis during infectious disease outbreaks like COVID-19.

Published
2020

37. Causal relationships between lipid and glycemic levels in an Indian population: A bidirectional Mendelian randomization approach

Author

Gagandeep Kaur Walia, Vipin Gupta, Shah Ebrahim, Tanica Lyngdoh, Tripti Agarwal, Sanjay Kinra, Dorairaj Prabhakaran, K. Srinath Reddy, George Davey Smith, Giriraj R. Chandak, Caroline L Relton, and Frank Dudbridge

Subjects
0301 basic medicine, Blood Glucose, Male, Genotyping Techniques, Physiology, Type 2 diabetes, 030204 cardiovascular system & hematology, Biochemistry, Fats, 0302 clinical medicine, Endocrinology, Glucose Metabolism, Medicine and Health Sciences, Insulin, Multidisciplinary, Alcohol Consumption, Mendelian Randomization Analysis, Lipids, 3. Good health, Type 2 Diabetes, Cholesterol, Medicine, Carbohydrate Metabolism, Female, Research Article, Adult, medicine.medical_specialty, Endocrine Disorders, Science, India, Single-nucleotide polymorphism, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, 03 medical and health sciences, Insulin resistance, Quantitative Trait, Heritable, Internal medicine, Mendelian randomization, medicine, Diabetes Mellitus, Humans, Least-Squares Analysis, Triglycerides, Glycemic, Nutrition, Diabetic Endocrinology, Endocrine Physiology, Cholesterol, HDL, Biology and Life Sciences, Cholesterol, LDL, medicine.disease, Hormones, Diet, 030104 developmental biology, Metabolism, Cross-Sectional Studies, Metabolic Disorders, Insulin Resistance, Dyslipidemia
Abstract

BackgroundDyslipidemia and abnormal glycemic traits are leading causes of morbidity and mortality. Although the association between the two traits is well established, there still exists a gap in the evidence for the direction of causality.ObjectiveThis study aimed to examine the direction of the causal relationship between lipids and glycemic traits in an Indian population using bidirectional Mendelian randomization (BMR).MethodsThe BMR analysis was conducted on 4900 individuals (2450 sib-pairs) from the Indian Migration Study. Instrument variables were generated for each lipid and glycemic trait (fasting insulin, fasting glucose, HOMA-IR, HOMA-β, LDL-cholesterol, HDL-cholesterol, total cholesterol and triglycerides) to examine the causal relationship by applying two-stage least squares (2SLS) regression in both directions.ResultsLipid and glycemic traits were found to be associated observationally, however, results from 2SLS showed that only triglycerides, defined by weighted genetic risk score (wGRS) of 3 SNPs (rs662799 at APOAV, rs780094 at GCKR and rs4420638 at APOE/C1/C4), were observed to be causally effecting 1.15% variation in HOMA-IR (SE = 0.22, P = 0.010), 1.53% in HOMA- β (SE = 0.21, P = 0.001) and 1.18% in fasting insulin (SE = 0.23, P = 0.009). No evidence for a causal effect was observed in the reverse direction or between any other lipid and glycemic traits.ConclusionThe study findings suggest that triglycerides may causally impact various glycemic traits. However, the findings need to be replicated in larger studies.

Published
2020

38. Novel p.P298L SURF1 mutation in thiamine deficient Leigh syndrome patients compromises cytochrome c oxidase activity

Author

Giriraj R. Chandak, Rajender Singh, Shalini Mani, S. Narasimha Rao, and Keshav K. Singh

Subjects
0301 basic medicine, Nuclear gene, India, Mitochondrion, medicine.disease_cause, Polymorphism, Single Nucleotide, Electron Transport Complex IV, Mitochondrial Proteins, 03 medical and health sciences, Exon, 0302 clinical medicine, Chlorocebus aethiops, medicine, Cytochrome c oxidase, Animals, Humans, SURF1, Genetic Predisposition to Disease, Child, Molecular Biology, Gene, Mutation, biology, Membrane Proteins, Thiamine Deficiency, Cell Biology, Molecular biology, 030104 developmental biology, COS Cells, biology.protein, Molecular Medicine, Thiamine, Leigh Disease, 030217 neurology & neurosurgery
Abstract

SURF1 is a nuclear gene and encodes for an important assembly factor for cytochrome c oxidase enzyme. A number of mutations in SURF1 gene render cytochrome c oxidase deficiency, a major causative factor for Leigh syndrome. We screened all the 9 exons and exon-intron boundaries of SURF1 gene in 165 Indian Leigh syndrome patients who were thiamine responsive too. Consequently, we identified several novel and reported nucleotide variations in this gene. The nucleotide changes were analysed by using different in-silico tools for predicting their pathogenicity. Based upon the predictions, we further validated the analyzed functional significance of p.N249D and p.P298L mutations in SURF1 protein using COS-7 cells. Though, both the mutations did not affect the localization of SURF1protein into the mitochondria. But, interestingly the novel mutation p.P298L was reported to significantly compromise the COX activity in these cells.

Published
2019

39. Associations of autozygosity with a broad range of human phenotypes

Author

Dennis O. Mook-Kanamori, Salma M. Wakil, Lisa R. Yanek, Dominique P.V. de Kleijn, Gert J. de Borst, Alison D. Murray, Kamran Guity, Vincent W. V. Jaddoe, Mario Pirastu, Carole Ober, Giuseppe Matullo, Charles N. Rotimi, Daniela Ruggiero, Teresa Tusié-Luna, Wolfgang Lieb, Chew-Kiat Heng, John R. B. Perry, Hortensia Moreno-Macías, Jie Zhou, John M. Starr, Juhani Junttila, Lei Yu, Danielle Posthuma, Marcus Dörr, Yingchang Lu, Jonathan P. Bradfield, Einat Granot-Hershkovitz, Karina Meidtner, Wouter van Rheenen, T Esko, Maris Alver, Wen-Jane Lee, Zhengming Chen, Jennifer A. Brody, Paolo Gasparini, Yii-Der Ida Chen, Cinzia Sala, Peter P. Pramstaller, Gauri Prasad, Nana Matoba, Natalie Terzikhan, Simonetta Guarrera, Bjarke Feenstra, Peter Vollenweider, Smeeta Shrestha, Yi-Jen Hung, Lilja Stefansdottir, David R. Weir, Felix R. Day, Antonietta Robino, Liang Zhang, Lluis Quintana-Murci, Nicholas J. Timpson, Robyn E Wootton, Xue W. Mei, Dharambir K. Sanghera, Gisli Masson, Debbie A Lawlor, Thomas Meitinger, Sharon L.R. Kardia, Peter K. Joshi, Frank J. A. van Rooij, Claude Bouchard, Cassandra N. Spracklen, Ken K. Ong, Taulant Muka, Guanjie Chen, Laura J. Scott, Walter Palmas, Daniel I. Chasman, Sarah E. Medland, Krista Fischer, Blair H. Smith, Jon K. Sigurdsson, Leon Straker, Clara Viberti, Yuan Shi, Louis Pérusse, Peter J. van der Most, Timo Tõnis Sikka, Chris Haley, Kuang Lin, Leif Groop, Hester M. den Ruijter, Hakon Hakonarson, Masato Akiyama, Stephan J. L. Bakker, Sonja I. Berndt, Jeffery R. O'Connell, Cisca Wijmenga, Daniele Cusi, Lorena Orozco, Kristjan H. S. Moore, Kevin Sandow, Stephen S. Rich, Stephanie J. Loomis, George Davey Smith, Cornelia M. van Duijn, Sharvari Rahul Shukla, Agnar Helgason, Thorsten Kessler, Anuj Goel, Dan Mason, David W. Clark, James S. Pankow, Simona Vaccargiu, Uwe Völker, Tamara B. Harris, Matthew A. Allison, Clicerio Gonzalez, Sarju Ralhan, I-Te Lee, Matthias Laudes, Yen-Feng Chiu, Neil Poulter, Benjamin Lehne, John Wright, Lawrence F. Bielak, Philip L. De Jager, Reinhold Schmidt, Ya Xing Wang, Matthias Nauck, Diana L. Cousminer, Patrick Deelen, Ani Manichaikul, Stephen J. Chanock, Anders Hamsten, Barry I. Freedman, Gudmar Thorleifsson, Peter Kraft, Ozren Polasek, Jie Yao, Yoshinori Murakami, Paul M. Ridker, Anubha Mahajan, Struan F.A. Grant, Claudia Schurmann, Bjarni Gunnarsson, Catriona L. K. Barnes, Jessica van Setten, Sandosh Padmanabhan, Alena Stančáková, Markus M. Lerch, Anuradha Jagadeesan, Franco Giulianini, Daniel F. Gudbjartsson, Dwaipayan Bharadwaj, Shengchao Alfred Li, Peter S. Sever, Trevor A. Mori, Albertine J. Oldehinkel, Koichi Matsuda, Xueling Sim, Evangelos Evangelou, André G. Uitterlinden, Pekka Jousilahti, Yukihide Momozawa, Ioanna Tzoulaki, Chao A. Hsiung, Ginevra Biino, Murielle Bochud, Hannele Mattsson, Ilja M. Nolte, Sarah H. Wild, Patricia B. Munroe, Jianjun Liu, Bruce M. Psaty, Giriraj R. Chandak, Masahiro Kanai, Tony R. Merriman, Teemu Palviainen, Rodney A. Lea, Janie Corley, Nicholas J. Wareham, Alan B. Zonderman, Makoto Hirata, Matthew J. Bixley, Caroline Hayward, Nora Franceschini, Kristel R van Eijk, Etienne Patin, Daniel Shriner, Niek Verweij, Xiuqing Guo, Fredrik Karpe, Ruth J. F. Loos, Tiinamaija Tuomi, Ashley van der Spek, Patricia A. Peyser, Jessica D. Faul, Christian Fuchsberger, David Cesarini, Alex S. F. Doney, Janine F. Felix, Cornelius A. Rietveld, Jagadish Vangipurapu, Tanguy Corre, Line Skotte, Rajkumar Dorajoo, Catherine Igartua, Meena Kumari, Nona Sotoodehnia, Leonard H. van den Berg, Najaf Amin, Dale R. Nyholt, Harry Campbell, Massimiliano Cocca, Scott D. Gordon, Patrik K. E. Magnusson, John C. Chambers, Traci M. Bartz, Mike A. Nalls, Tin Aung, Nduna Dzimiri, Colin N. A. Palmer, Rob M. van Dam, Johanna Kuusisto, Russell P. Tracy, Anna Damulina, Pierre-Emmanuel Morange, Sylvain Foisy, Jing Hua Zhao, Nicholas G. Martin, Ching-Yu Cheng, Mariaelisa Graff, Rashmi B. Prasad, Alice Stanton, David-Alexandre Trégouët, Yu Guo, Helen R. Warren, Lyn R. Griffiths, Weihua Meng, Annika Tillander, Christa Meisinger, Albert V. Smith, Mark I. McCarthy, Jingyun Yang, Marine Germain, Neil Small, Linda Broer, Vilmundur Gudnason, Gunnar K. Pálsson, Michele K. Evans, Alexander Teumer, Mark J. Caulfield, Giorgia Girotto, Thomas Lumley, Tinca J. C. Polderman, Wei Zhao, Carlos A. Aguilar-Salinas, Jari Lahti, Matthew L. Albert, Yechiel Friedlander, Veikko Salomaa, Iona Y Millwood, Jan H. Veldink, Archie Campbell, Andres Metspalu, Ulf Gyllensten, Grant W. Montgomery, Veronique Vitart, Jai Rup Singh, Saima Afaq, Alan R. Shuldiner, Miao-Li Chee, Adebowale Adeyemo, Jennifer A. Smith, David A. van Heel, Jaspal S. Kooner, Daniela Toniolo, Cristian Pattaro, Jerome I. Rotter, John Whitfield, Melissa C. Smart, Kari E. North, Salman M. Tajuddin, Tallapragada Divya Sri Priyanka, Christopher A. Haiman, Diane M. Becker, Bernhard K. Krämer, Paul Elliott, Lihua Wang, He Gao, Patrick Sulem, Jinyan Huang, Chiea Chuen Khor, Ruifang Li-Gao, Åsa Johansson, Winfried März, Shai Carmi, Ilaria Gandin, Eric Boerwinkle, Gardar Sveinbjornsson, Saskia P. Hagenaars, Sander W. van der Laan, Gerard Pasterkamp, E-Shyong Tai, Hagit Hochner, Yih Chung Tham, Kent D. Taylor, Kari Stefansson, Matt J. Neville, Craig E. Pennell, Yanchun Bao, Annelot M. Dekker, Helena Schmidt, Mehdi Hedayati, Joshua Elliott, Ian J. Deary, Iris E. Jansen, Judith B. Borja, Edith Hofer, Martin Gögele, Igor Rudan, Lude Franke, Matthias Munz, Folkert W. Asselbergs, Bengt Sennblad, Imo Hofer, John D. Rioux, Pim van der Harst, Bahareh Sedaghati-khayat, Giovanni Cugliari, Morris A. Swertz, Francine Grodstein, Erwin P. Bottinger, Carol A. Wang, Andre Franke, Brian F. Meyer, Adele M. Taylor, Klodian Dhana, Jian'an Luan, Constance Turman, Robert A. Scott, May E. Montasser, Alison Pattie, Marco Brumat, Liming Li, Heiner Boeing, Karen L. Mohlke, Clemens Baumbach, Bishwa Raj Sapkota, Unnur Thorsteinsdottir, Naveed Sattar, Amy R. Bentley, Matthias B. Schulze, Ivana Kolcic, Stella Trompet, Sarah E. Harris, Ayo P. Doumatey, Charumathi Sabanayagam, David Eccles, Mary F. Feitosa, Jost B. Jonas, Massimo Mezzavilla, Mark O. Goodarzi, David Ellinghaus, Heribert Schunkert, Christian Gieger, Heikki V. Huikuri, Lingyao Zeng, Johan G. Eriksson, Woon-Puay Koh, Yucheng Jia, Gurpreet Singh Wander, James F. Wilson, Torgny Karlsson, Steven C. Hunt, Weihua Zhang, Maria Pina Concas, Zoltán Kutalik, Rebecca Rohde, Chittaranjan S. Yajnik, Yasaman Saba, Dabeeru C. Rao, Robin G. Walters, Reedik Mägi, Marie Loh, Eero Vuoksimaa, Josyf C. Mychaleckyj, Katri Räikkönen, Philippe Goyette, M. Arfan Ikram, Alicia Huerta-Chagoya, David J. Porteous, Teresa Nutile, J. Wouter Jukema, Noha A. Yousri, Yoichiro Kamatani, Maryam S. Daneshpour, Babette S. Zemel, Rona J. Strawbridge, Tien Yin Wong, Claudia Langenberg, Amy Moore, Marcus E. Kleber, Fereidoun Azizi, Avner Halevy, Erika Salvi, Francis S. Collins, Markku Laakso, Tim Kacprowski, S. Sunna Ebenesersdóttir, William R. Scott, Michael Boehnke, Jin-Fang Chai, Markus Perola, Nicola Pirastu, Wayne Huey-Herng Sheu, Robert Karlsson, Lenore J. Launer, Lili Milani, Renée de Mutsert, Fernando Rivadeneira, David A. Bennett, Nicola D. Kerrison, Paolo Manunta, Graciela E. Delgado, Magnus Johannesson, Carolina Medina-Gomez, Alanna C. Morrison, Kay-Tee Khaw, Jian-Min Yuan, Jaakko Kaprio, Melanie Waldenberger, Ralf Ewert, Hugoline G. de Haan, Andrew A. Hicks, Yukinori Okada, Maria Sabater-Lleal, Marilyn C. Cornelis, Stephanie J. London, Federica Rizzi, Jeanette Erdmann, Marina Ciullo, Michiaki Kubo, University of Edinburgh, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Osaka University Graduate School of Medicine, Laboratory for Cardiovascular Genomics and Informatics [Yokohama] (RIKEN IMS), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN)-RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), deCODE genetics [Reykjavik], Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR), Area Science Park, Università degli studi di Trieste = University of Trieste, MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Harbor UCLA Medical Center [Torrance, Ca.], Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, Department of Electrical and Computer Engineering [Waterloo] (ECE), University of Waterloo [Waterloo], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Institute of Pop. Genetics, CNR, Sassari, Shardna life science Pula Cagliari, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Medstar Research Institute, Florida State University [Tallahassee] (FSU), University Medical Center [Utrecht], Centre for Population Health Sciences, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), California State University [Sacramento], Department of Thrombosis and Haemostasis, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Medical University Graz, Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Heidelberg, Frederick National Laboratory for Cancer Research (FNLCR), Wellcome Trust Centre of Human Genetics, University of Oxford, Department of Epidemiology, German Institute of Human Nutrition, University Medical Center Groningen [Groningen] (UMCG), Institute of Genetics and Biophysics, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Department of Medicine, Surgery, and Dentistry, University of Milano, Icelandic Heart Association, Kopavogur, Iceland., Department of Epidemiology [Rotterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Glasgow, Department of Cardiology, Leiden University Medical Center, Leiden, Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, Queen Mary University of London (QMUL), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Institut de biologie moléculaire des plantes (IBMP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Genentech, Inc., Genentech, Inc. [San Francisco], University of Tartu, Duke-NUS Medical School [Singapore], Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Human Genome Sequencing Center, Baylor College of Medicine, Baylor College of Medicine (BCM), Baylor University-Baylor University, University of San Carlos, Office of Population Studies Foundation, Icahn School of Medicine at Mount Sinai [New York] (MSSM), King‘s College London, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), University of Oxford, Vth Department of Medicine (Nephrology, Hypertensiology, Endocrinology, Diabetology, Rheumatology), Medical Faculty of Mannheim, University of Heidelberg, Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Department of Internal Medicine B, University Medicine Greifswald, Greifswald, University of Chicago, University of Huddersfield, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Section on Nephrology [Winston-Salem, NC, USA] (Department of Internal Medicine), Wake Forest School of Medicine [Winston-Salem], Wake Forest Baptist Medical Center-Wake Forest Baptist Medical Center, Radcliffe Department of Medicine [Oxford], Harvard School of Public Health, Kunming University of Science and Technology (KMUST), Sans affiliation, University of Southern California (USC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), MRC Centrer for Nutritional Epidemiology and Cancer Prevention and Survival, University of Cambridge [UK] (CAM), National University of Singapore (NUS), Experimental Cardiology Laboratory (ECL), Unirversity Medical Center, Department of Medical Statistics, Epidemiology and Medical Informatics, University of Zagreb, Department of Medical Genetics, Department of Medicine, University of Eastern Finland-Kuopio University Hospital, MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Capital Normal University [Beijing], Saw Swee Hock School of Public Health, National Institute for Environmental Health Sciences Research Triangle Park, Brown University, MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, Toyota Research Institute, Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Metacohorts Consortium, Universiteit Leiden, Institute of Clinical Chemistry and Laboratory Medicine, University of Groningen [Groningen], Medical Research Concil Epidemiology Unit, Institute of Medical Science, Faculty of Medicine, Genetics and Pathology, Imperial College London, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Brigham and Women's Hospital [Boston], Erasmus University Rotterdam, Department of Chronic Disease Prevention, National Institute for Health and Welfare [Helsinki], Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Stockholm Bioinformatics Center (SBC), Stockholm University, Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, INRH, Department of Genetics, Los Angeles Biomedical Research Institute (LA BioMed), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Western General Hospital, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Medical Research Council, Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute-University of Pittsburgh Graduate School of Public Health, Zhengzhou University of Light Industry, Department of Electrical and Electronic Engineering [Niigata Univ.], Niigata University, Genetic Epidemiology Unit, University College of London [London] (UCL), Aston Business School, Aston University [Birmingham], Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], Centre Hospitalier Universitaire Vaudois (CHUV), Pennington Biomedical Research Center, University of Washington [Seattle], Guy's and St Thomas' Hospitals, Northwestern Polytechnical University [Xi'an] (NPU), Department of Social Medicine, University of Bristol [Bristol], Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Department of Internal Medicine, Institute of Clinical Molecular Biology, Kiel University, Medizinische Klinik II, Universität zu Lübeck = University of Lübeck [Lübeck], Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina, Institute for Social Research, University of Michigan System-University of Michigan System, Division of Statistical Genomics, Washington University School of Medicine, Institute for Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel (CAU), Department of Physics, RISSC-Lab-University of Naples Federico II = Università degli studi di Napoli Federico II, Lund University [Lund], Icelandic Heart Association, Heart Preventive Clinic and Research Institute, The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Medical Research Center Oulu, University of Oulu, University of Utah School of Medicine [Salt Lake City], The Generation R Study, Pediatrics, Epidemiology, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], Universität Heidelberg [Heidelberg] = Heidelberg University, Interuniversity Cardiology Institute Netherlands, School of Public Health, University of Michigan [Dearborn], Department of Epidemiology and Public Health, University of Kuopio, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Epidemiology and Biobank PopGen, Department of Biostatistics, University of Washington, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Clinical Institute of Medical and Chemical Laboratory Diagnostics, Karl-Franzens-Universität Graz, Department of Genetics, Biology and Biochemistry, Università degli studi di Torino = University of Turin (UNITO), Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), QIMR Berghofer Medical Research Institute, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC)-UNC Gillings School of Global Public Health-Carolina Center for Genome Sciences, University of Illinois [Chicago] (UIC), University of Illinois System, Experimental Cardiology Laboratory, Genetic Epidemiology and Clinical Research Group, Umea University Hospital, Functional Genomics, Erasmus Medical Centre, National Human Genome Research Institute (NHGRI), School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Department of Pathological Biochemistry, Royal Infirmary, German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), Institute of Metabolic Science, MRC, University of Maryland School of Medicine [Baltimore, MD, USA], Centre for Molecular Epidemiology, Centre for Causal Analyses in Translational Epidemiology, University of Bristol [Bristol]-Medical Research Council, IRCCS San Raffaele Scientific Institute [Milan, Italie], U937, Génomique cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), University of Michigan System, HMNC Brain Health, Singapore Eye Research Institute, Partenaires INRAE, Institut d'Électronique et des Technologies du numéRique (IETR), Université de Nantes (UN)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Department of Psychiatry and Psychotherapy, Rheinische Friedrich-Wilhelms-Universität Bonn, University of Groningen, Department of Genomics of Common Disease, Department of Microbiology, The Freeman Hospital, Department Biostatistics University of North Carolina, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Clark, D. W., Okada, Y., Moore, K. H. S., Mason, D., Pirastu, N., Gandin, I., Mattsson, H., Barnes, C. L. K., Lin, K., Zhao, J. H., Deelen, P., Rohde, R., Schurmann, C., Guo, X., Giulianini, F., Zhang, W., Medina-Gomez, C., Karlsson, R., Bao, Y., Bartz, T. M., Baumbach, C., Biino, G., Bixley, M. J., Brumat, M., Chai, J. -F., Corre, T., Cousminer, D. L., Dekker, A. M., Eccles, D. A., van Eijk, K. R., Fuchsberger, C., Gao, H., Germain, M., Gordon, S. D., de Haan, H. G., Harris, S. E., Hofer, E., Huerta-Chagoya, A., Igartua, C., Jansen, I. E., Jia, Y., Kacprowski, T., Karlsson, T., Kleber, M. E., Li, S. A., Li-Gao, R., Mahajan, A., Matsuda, K., Meidtner, K., Meng, W., Montasser, M. E., van der Most, P. J., Munz, M., Nutile, T., Palviainen, T., Prasad, G., Prasad, R. B., Priyanka, T. D. S., Rizzi, F., Salvi, E., Sapkota, B. R., Shriner, D., Skotte, L., Smart, M. C., Smith, A. V., van der Spek, A., Spracklen, C. N., Strawbridge, R. J., Tajuddin, S. M., Trompet, S., Turman, C., Verweij, N., Viberti, C., Wang, L., Warren, H. R., Wootton, R. E., Yanek, L. R., Yao, J., Yousri, N. A., Zhao, W., Adeyemo, A. A., Afaq, S., Aguilar-Salinas, C. A., Akiyama, M., Albert, M. L., Allison, M. A., Alver, M., Aung, T., Azizi, F., Bentley, A. R., Boeing, H., Boerwinkle, E., Borja, J. B., de Borst, G. J., Bottinger, E. P., Broer, L., Campbell, H., Chanock, S., Chee, M. -L., Chen, G., Chen, Y. -D. I., Chen, Z., Chiu, Y. -F., Cocca, M., Collins, F. S., Concas, M. P., Corley, J., Cugliari, G., van Dam, R. M., Damulina, A., Daneshpour, M. S., Day, F. R., Delgado, G. E., Dhana, K., Doney, A. S. F., Dorr, M., Doumatey, A. P., Dzimiri, N., Ebenesersdottir, S. S., Elliott, J., Elliott, P., Ewert, R., Felix, J. F., Fischer, K., Freedman, B. I., Girotto, G., Goel, A., Gogele, M., Goodarzi, M. O., Graff, M., Granot-Hershkovitz, E., Grodstein, F., Guarrera, S., Gudbjartsson, D. F., Guity, K., Gunnarsson, B., Guo, Y., Hagenaars, S. P., Haiman, C. A., Halevy, A., Harris, T. B., Hedayati, M., van Heel, D. A., Hirata, M., Hofer, I., Hsiung, C. A., Huang, J., Hung, Y. -J., Ikram, M. A., Jagadeesan, A., Jousilahti, P., Kamatani, Y., Kanai, M., Kerrison, N. D., Kessler, T., Khaw, K. -T., Khor, C. C., de Kleijn, D. P. V., Koh, W. -P., Kolcic, I., Kraft, P., Kramer, B. K., Kutalik, Z., Kuusisto, J., Langenberg, C., Launer, L. J., Lawlor, D. A., Lee, I. -T., Lee, W. -J., Lerch, M. M., Li, L., Liu, J., Loh, M., London, S. J., Loomis, S., Lu, Y., Luan, J., Magi, R., Manichaikul, A. W., Manunta, P., Masson, G., Matoba, N., Mei, X. W., Meisinger, C., Meitinger, T., Mezzavilla, M., Milani, L., Millwood, I. Y., Momozawa, Y., Moore, A., Morange, P. -E., Moreno-Macias, H., Mori, T. A., Morrison, A. C., Muka, T., Murakami, Y., Murray, A. D., de Mutsert, R., Mychaleckyj, J. C., Nalls, M. A., Nauck, M., Neville, M. J., Nolte, I. M., Ong, K. K., Orozco, L., Padmanabhan, S., Palsson, G., Pankow, J. S., Pattaro, C., Pattie, A., Polasek, O., Poulter, N., Pramstaller, P. P., Quintana-Murci, L., Raikkonen, K., Ralhan, S., Rao, D. C., van Rheenen, W., Rich, S. S., Ridker, P. M., Rietveld, C. A., Robino, A., van Rooij, F. J. A., Ruggiero, D., Saba, Y., Sabanayagam, C., Sabater-Lleal, M., Sala, C. F., Salomaa, V., Sandow, K., Schmidt, H., Scott, L. J., Scott, W. R., Sedaghati-Khayat, B., Sennblad, B., van Setten, J., Sever, P. J., Sheu, W. H. -H., Shi, Y., Shrestha, S., Shukla, S. R., Sigurdsson, J. K., Sikka, T. T., Singh, J. R., Smith, B. H., Stancakova, A., Stanton, A., Starr, J. M., Stefansdottir, L., Straker, L., Sulem, P., Sveinbjornsson, G., Swertz, M. A., Taylor, A. M., Taylor, K. D., Terzikhan, N., Tham, Y. -C., Thorleifsson, G., Thorsteinsdottir, U., Tillander, A., Tracy, R. P., Tusie-Luna, T., Tzoulaki, I., Vaccargiu, S., Vangipurapu, J., Veldink, J. H., Vitart, V., Volker, U., Vuoksimaa, E., Wakil, S. M., Waldenberger, M., Wander, G. S., Wang, Y. X., Wareham, N. J., Wild, S., Yajnik, C. S., Yuan, J. -M., Zeng, L., Zhang, L., Zhou, J., Amin, N., Asselbergs, F. W., Bakker, S. J. L., Becker, D. M., Lehne, B., Bennett, D. A., van den Berg, L. H., Berndt, S. I., Bharadwaj, D., Bielak, L. F., Bochud, M., Boehnke, M., Bouchard, C., Bradfield, J. P., Brody, J. A., Campbell, A., Carmi, S., Caulfield, M. J., Cesarini, D., Chambers, J. C., Chandak, G. R., Cheng, C. -Y., Ciullo, M., Cornelis, M., Cusi, D., Smith, G. D., Deary, I. J., Dorajoo, R., van Duijn, C. M., Ellinghaus, D., Erdmann, J., Eriksson, J. G., Evangelou, E., Evans, M. K., Faul, J. D., Feenstra, B., Feitosa, M., Foisy, S., Franke, A., Friedlander, Y., Gasparini, P., Gieger, C., Gonzalez, C., Goyette, P., Grant, S. F. A., Griffiths, L. R., Groop, L., Gudnason, V., Gyllensten, U., Hakonarson, H., Hamsten, A., van der Harst, P., Heng, C. -K., Hicks, A. A., Hochner, H., Huikuri, H., Hunt, S. C., Jaddoe, V. W. V., De Jager, P. L., Johannesson, M., Johansson, A., Jonas, J. B., Jukema, J. W., Junttila, J., Kaprio, J., Kardia, S. L. R., Karpe, F., Kumari, M., Laakso, M., van der Laan, S. W., Lahti, J., Laudes, M., Lea, R. A., Lieb, W., Lumley, T., Martin, N. G., Marz, W., Matullo, G., Mccarthy, M. I., Medland, S. E., Merriman, T. R., Metspalu, A., Meyer, B. F., Mohlke, K. L., Montgomery, G. W., Mook-Kanamori, D., Munroe, P. B., North, K. E., Nyholt, D. R., O'Connell, J. R., Ober, C., Oldehinkel, A. J., Palmas, W., Palmer, C., Pasterkamp, G. G., Patin, E., Pennell, C. E., Perusse, L., Peyser, P. A., Pirastu, M., Polderman, T. J. C., Porteous, D. J., Posthuma, D., Psaty, B. M., Rioux, J. D., Rivadeneira, F., Rotimi, C., Rotter, J. I., Rudan, I., Den Ruijter, H. M., Sanghera, D. K., Sattar, N., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, R. A., Shuldiner, A. R., Sim, X., Small, N., Smith, J. A., Sotoodehnia, N., Tai, E. -S., Teumer, A., Timpson, N. J., Toniolo, D., Tregouet, D. -A., Tuomi, T., Vollenweider, P., Wang, C. A., Weir, D. R., Whitfield, J. B., Wijmenga, C., Wong, T. -Y., Wright, J., Yang, J., Yu, L., Zemel, B. S., Zonderman, A. B., Perola, M., Magnusson, P. K. E., Uitterlinden, A. G., Kooner, J. S., Chasman, D. I., Loos, R. J. F., Franceschini, N., Franke, L., Haley, C. S., Hayward, C., Walters, R. G., Perry, J. R. B., Esko, T., Helgason, A., Stefansson, K., Joshi, P. K., Kubo, M., Wilson, J. F., Læknadeild (HÍ), Faculty of Medicine (UI), Félagsfræði-, mannfræði- og þjóðfræðideild (HÍ), Faculty of Sociology, Anthropology and Folkloristics (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Félagsvísindasvið (HÍ), School of Social Sciences (UI), Háskóli Íslands, University of Iceland, Clark, David W [0000-0002-1025-9185], Okada, Yukinori [0000-0002-0311-8472], Moore, Kristjan H S [0000-0002-9579-4362], Mason, Dan [0000-0002-0026-9216], Pirastu, Nicola [0000-0002-5363-3886], Gandin, Ilaria [0000-0003-3196-2491], Deelen, Patrick [0000-0002-5654-3966], Schurmann, Claudia [0000-0003-4158-9192], Medina-Gomez, Carolina [0000-0001-7999-5538], Karlsson, Robert [0000-0002-8949-2587], Bao, Yanchun [0000-0002-6102-5098], Biino, Ginevra [0000-0002-9936-946X], Brumat, Marco [0000-0003-3268-039X], Chai, Jin-Fang [0000-0003-3770-1137], Eccles, David A [0000-0003-4634-4995], Gordon, Scott D [0000-0001-7623-328X], Harris, Sarah E [0000-0002-4941-5106], Kacprowski, Tim [0000-0002-5393-2413], Karlsson, Torgny [0000-0001-8095-6149], Kleber, Marcus E [0000-0003-0663-7275], Mahajan, Anubha [0000-0001-5585-3420], Matsuda, Koichi [0000-0001-7292-2686], Meng, Weihua [0000-0001-5388-8494], van der Most, Peter J [0000-0001-8450-3518], Munz, Matthias [0000-0002-4728-3357], Palviainen, Teemu [0000-0002-7847-8384], Prasad, Rashmi B [0000-0002-4400-6741], Salvi, Erika [0000-0002-2724-2291], Skotte, Line [0000-0002-7398-1271], van der Spek, Ashley [0000-0001-7136-0159], Spracklen, Cassandra N [0000-0003-3590-7182], Strawbridge, Rona J [0000-0001-8506-3585], Tajuddin, Salman M [0000-0002-7919-8528], Verweij, Niek [0000-0002-4303-7685], Yanek, Lisa R [0000-0001-7117-1075], Zhao, Wei [0000-0001-7388-0692], Albert, Matthew L [0000-0001-7285-6973], Bentley, Amy R [0000-0002-0827-9101], Chanock, Stephen [0000-0002-2324-3393], Chen, Zhengming [0000-0001-6423-105X], Chiu, Yen-Feng [0000-0002-3352-4500], Cocca, Massimiliano [0000-0002-1127-7596], Collins, Francis S [0000-0002-1023-7410], Cugliari, Giovanni [0000-0002-6080-0718], Damulina, Anna [0000-0001-8241-2727], Day, Felix R [0000-0003-3789-7651], Dhana, Klodian [0000-0002-6397-7009], Dzimiri, Nduna [0000-0003-3395-5754], Elliott, Paul [0000-0002-7511-5684], Felix, Janine F [0000-0002-9801-5774], Freedman, Barry I [0000-0003-0275-5530], Girotto, Giorgia [0000-0003-4507-6589], Goel, Anuj [0000-0003-2307-4021], Goodarzi, Mark O [0000-0001-6364-5103], Gudbjartsson, Daniel F [0000-0002-5222-9857], Guity, Kamran [0000-0002-8379-9668], van Heel, David A [0000-0002-0637-2265], Hirata, Makoto [0000-0002-9994-9958], Ikram, M Arfan [0000-0003-0372-8585], Kamatani, Yoichiro [0000-0001-8748-5597], Kanai, Masahiro [0000-0001-5165-4408], Khor, Chiea Chuen [0000-0002-1128-4729], Kolcic, Ivana [0000-0001-7918-6052], Langenberg, Claudia [0000-0002-5017-7344], Lawlor, Deborah A [0000-0002-6793-2262], Liu, Jianjun [0000-0002-3255-3019], London, Stephanie J [0000-0003-4911-5290], Luan, Jian’an [0000-0003-3137-6337], Matoba, Nana [0000-0001-5329-0134], Mei, Xue W [0000-0002-6279-4884], Mezzavilla, Massimo [0000-0002-9000-4595], Milani, Lili [0000-0002-5323-3102], Mori, Trevor A [0000-0002-5264-9229], Murakami, Yoshinori [0000-0002-2826-4396], Murray, Alison D [0000-0003-4915-4847], Mychaleckyj, Josyf C [0000-0003-2595-0005], Neville, Matt J [0000-0002-6004-5433], Nolte, Ilja M [0000-0001-5047-4077], Ong, Ken K [0000-0003-4689-7530], Pálsson, Gunnar [0000-0002-8231-3961], Pankow, James S [0000-0001-7076-483X], Pattaro, Cristian [0000-0002-4119-0109], Quintana-Murci, Lluis [0000-0003-2429-6320], van Rheenen, Wouter [0000-0002-5860-1533], Rich, Stephen S [0000-0003-3872-7793], Rietveld, Cornelius A [0000-0003-4053-1861], Ruggiero, Daniela [0000-0003-3898-7827], Sabanayagam, Charumathi [0000-0002-4042-4719], Sabater-Lleal, Maria [0000-0002-0128-379X], Sala, Cinzia Felicita [0000-0003-2514-2075], Salomaa, Veikko [0000-0001-7563-5324], Scott, Laura J [0000-0002-4886-5084], Sedaghati-Khayat, Bahareh [0000-0002-7665-8648], Sennblad, Bengt [0000-0002-4360-8003], van Setten, Jessica [0000-0002-4934-7510], Smith, Blair H [0000-0002-5362-9430], Stančáková, Alena [0000-0002-1375-0252], Stanton, Alice [0000-0002-4961-165X], Straker, Leon [0000-0002-7786-4128], Sulem, Patrick [0000-0001-7123-6123], Swertz, Morris A [0000-0002-0979-3401], Taylor, Kent D [0000-0002-2756-4370], Tzoulaki, Ioanna [0000-0002-4275-9328], Veldink, Jan H [0000-0001-5572-9657], Vitart, Veronique [0000-0002-4991-3797], Völker, Uwe [0000-0002-5689-3448], Wander, Gurpreet S [0000-0002-4596-4247], Wang, Ya Xing [0000-0003-2749-7793], Wild, Sarah [0000-0001-7824-2569], Yuan, Jian-Min [0000-0002-4620-3108], Asselbergs, Folkert W [0000-0002-1692-8669], Boehnke, Mike [0000-0002-6442-7754], Bouchard, Claude [0000-0002-0048-491X], Brody, Jennifer A [0000-0001-8509-148X], Campbell, Archie [0000-0003-0198-5078], Caulfield, Mark J [0000-0001-9295-3594], Smith, George Davey [0000-0002-1407-8314], Dorajoo, Rajkumar [0000-0001-6608-2051], Ellinghaus, David [0000-0002-4332-6110], Erdmann, Jeanette [0000-0002-4486-6231], Evangelou, Evangelos [0000-0002-5488-2999], Feenstra, Bjarke [0000-0003-1478-649X], Feitosa, Mary [0000-0002-0933-2410], Franke, Andre [0000-0003-1530-5811], Grant, Struan F A [0000-0003-2025-5302], Griffiths, Lyn R [0000-0002-6774-5475], Groop, Leif [0000-0002-0187-3263], Gudnason, Vilmundur [0000-0001-5696-0084], van der Harst, Pim [0000-0002-2713-686X], Heng, Chew-Kiat [0000-0002-7309-9473], Hicks, Andrew A [0000-0001-6320-0411], Jaddoe, Vincent W V [0000-0003-2939-0041], De Jager, Philip L [0000-0002-8057-2505], Johannesson, Magnus [0000-0001-8759-6393], Johansson, Åsa [0000-0002-2915-4498], Jonas, Jost B [0000-0003-2972-5227], Jukema, J Wouter [0000-0002-3246-8359], Kaprio, Jaakko [0000-0002-3716-2455], Laakso, Markku [0000-0002-3394-7749], van der Laan, Sander W [0000-0001-6888-1404], Lahti, Jari [0000-0002-4310-5297], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Merriman, Tony R [0000-0003-0844-8726], Metspalu, Andres [0000-0002-3718-796X], Mohlke, Karen L [0000-0001-6721-153X], Montgomery, Grant W [0000-0002-4140-8139], Munroe, Patricia B [0000-0002-4176-2947], Nyholt, Dale R [0000-0001-7159-3040], Ober, Carole [0000-0003-4626-9809], Oldehinkel, Albertine J [0000-0003-3925-3913], Palmer, Colin [0000-0002-6415-6560], Perusse, Louis [0000-0001-6440-9698], Polderman, Tinca J. C. [0000-0001-5564-301X], Porteous, David J [0000-0003-1249-6106], Rioux, John D [0000-0001-7560-8326], Rivadeneira, Fernando [0000-0001-9435-9441], Rotimi, Charles [0000-0001-5759-053X], Rotter, Jerome I [0000-0001-7191-1723], Rudan, Igor [0000-0001-6993-6884], Sattar, Naveed [0000-0002-1604-2593], Sim, Xueling [0000-0002-1233-7642], Smith, Jennifer A [0000-0002-3575-5468], Teumer, Alexander [0000-0002-8309-094X], Timpson, Nicholas J [0000-0002-7141-9189], Tuomi, Tiinamaija [0000-0002-8306-6202], Wang, Carol A [0000-0002-4301-3974], Weir, David R [0000-0002-1661-2402], Whitfield, John B [0000-0002-1103-0876], Magnusson, Patrik K. E. [0000-0002-7315-7899], Uitterlinden, André G [0000-0002-7276-3387], Loos, Ruth J. F. [0000-0002-8532-5087], Franke, Lude [0000-0002-5159-8802], Haley, Chris S [0000-0002-9811-0210], Hayward, Caroline [0000-0002-9405-9550], Walters, Robin G [0000-0002-9179-0321], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Apollo - University of Cambridge Repository, Moore, Kristjan HS [0000-0002-9579-4362], Luan, Jian'an [0000-0003-3137-6337], Grant, Struan FA [0000-0003-2025-5302], Jaddoe, Vincent WV [0000-0003-2939-0041], Polderman, Tinca JC [0000-0001-5564-301X], Magnusson, Patrik KE [0000-0002-7315-7899], Loos, Ruth JF [0000-0002-8532-5087], Neurology, Human genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), Lifestyle Medicine (LM), Groningen Kidney Center (GKC), Cardiovascular Centre (CVC), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Stem Cell Aging Leukemia and Lymphoma (SALL), Institute for Molecular Medicine Finland, Department of Psychology and Logopedics, University Management, Developmental Psychology Research Group, Staff Services, Cognitive and Brain Aging, Research Programs Unit, Diabetes and Obesity Research Program, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Department of Public Health, Genetic Epidemiology, Helsinki Collegium for Advanced Studies, HUS Abdominal Center, Endokrinologian yksikkö, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), University of Trieste, Université de Lausanne (UNIL), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Consiglio Nazionale delle Ricerche (CNR), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Institut Pasteur [Paris], University of Oxford [Oxford], Medical Genetics, Dept. RSD and Public Health, IRCCS-Burlo Garofolo/University of Trieste, sans affiliation, Helmholtz-Zentrum München (HZM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institute of Cardiovascular Science, University College London, Hammersmith Hospital NHS Imperial College Healthcare-Imperial College London, Universität zu Lübeck [Lübeck], University of Ioannina Medical School, Università degli studi di Napoli Federico II-RISSC-Lab, Universität Heidelberg [Heidelberg], University of Turin, University of California-University of California, Nantes Université (NU)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), University of Helsinki-University of Helsinki, Université de Nantes (UN)-Université de Rennes 1 (UR1), Erasmus MC other, Internal Medicine, and Applied Economics

Subjects
0301 basic medicine, 631/208/1397, Chemistry(all), Health Status, [SDV]Life Sciences [q-bio], LOCI, General Physics and Astronomy, MESH: Haplotype, MESH: Cognition, 030105 genetics & heredity, Runs of Homozygosity, Biochemistry, Consanguinity, Cognition, Inbreeding depression, 2.1 Biological and endogenous factors, Body Size, Inbreeding, Skyldleikarækt, Aetiology, Human phenotypes, lcsh:Science, MESH: Health Status, Genetics, Multidisciplinary, Inbreeding Depression, Confounding, Homozygote, RUNS, 631/208/205, 631/208/721, 3. Good health, genomic inbreeding coefficients, MESH: Risk-Taking, 631/208/730, Autozygosit, homozygosity, Erfðarannsóknir, Medical Genetics, genomic inbreeding coefficient, MESH: Homozygote, Offspring, Science, Autozygosity, Blóðsifjar, 610 Medicine & health, Biology, INBREEDING DEPRESSION, HOMOZYGOSITY, FERTILITY, QUANTIFICATION, Physics and Astronomy(all), General Biochemistry, Genetics and Molecular Biology, Article, Association, 03 medical and health sciences, Risk-Taking, 360 Social problems & social services, Journal Article, Humans, ddc:610, Allele, Alleles, Medicinsk genetik, Genetic association study, MESH: Consanguinity, MESH: Body Size, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), MESH: Alleles, Haplotype, MESH: Fertility, General Chemistry, Brain Disorders, MESH: Inbreeding Depression, 030104 developmental biology, Fertility, Haplotypes, Genetic markers, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, 3111 Biomedicine, Genetics and Molecular Biology(all)
Abstract

Publisher's version (útgefin grein)., In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding., This paper is the work of the ROHgen consortium. We thank the Sigma T2D Consortium, whose members are detailed in Supplementary Note 3. We thank the UK Biobank Resource, approved under application 19655; we acknowledge funding from the UK Medical Research Council Human Genetics Unit and MRC Doctoral Training Programme in Precision Medicine. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial. Finally, we thank all the participants, researchers and funders of ROHgen cohorts. Cohort-specific acknowledgements are in Supplementary Data 2; personal acknowledgements and disclosures are in Supplementary Note 2. We thank Rachel Edwards for administrative assistance.

Published
2019

40. Identification and characterization of cis-regulatory elements ‘insulator and repressor’ in PPARD gene

Author

Gunjan Dadhwal, Smeeta Shrestha, Giriraj R. Chandak, and Dilip K. Yadav

Subjects
0301 basic medicine, Cancer Research, Reporter gene, Genome, Human, Intron, Repressor, Computational biology, Insulator (genetics), Biology, 03 medical and health sciences, Enhancer Elements, Genetic, 030104 developmental biology, PPARD Gene, Genetics, Humans, Insulator Elements, Human genome, Peroxisome proliferator-activated receptor delta, PPAR delta, Enhancer
Abstract

Aim: Identification and functional characterization of cis-regulatory elements in human PPARD gene. Methods: We used various bioinformatic tools on the publicly available human genome and Encyclopedia of DNA Elements databases to explore potential cis-regulatory elements in PPARD gene region. Results: We predicted an insulator and an enhancer element in intron 2 of PPARD gene. Functional characterization using transient transfection, reporter assay and CTCF binding confirmed the insulator status. However, the predicted enhancer element showed repressor/silencer activity. Finally, we observed a potential interaction between these two cis-regulatory elements which is in agreement with 5C-Encyclopedia of DNA Elements data. Conclusion: We report two functionally validated cis-regulatory elements in PPARD gene which will aid in understanding its regulation and role in metabolic functions.

Published
2018

41. Inclusion of Population-specific Reference Panel from India to the 1000 Genomes Phase 3 Panel Improves Imputation Accuracy

Author

Vikrant Kumar, Chittaranjan S. Yajnik, Sreya Ghosh, Sonia Davila, Meraj Ahmad, Giriraj R. Chandak, and Anubhav Sinha

Subjects
0301 basic medicine, Asia, Computer science, Science, Population, Correlation and dependence, Genome-wide association study, computer.software_genre, Article, White People, 03 medical and health sciences, Asian People, Gene Frequency, Reference Values, Human Genome Project, Humans, Imputation (statistics), 1000 Genomes Project, education, Allele frequency, Alleles, education.field_of_study, Multidisciplinary, Genome, Human, Haplotype, Computational Biology, Genetic Variation, High-Throughput Nucleotide Sequencing, 030104 developmental biology, Genetics, Population, Haplotypes, Medicine, Data mining, computer, Imputation (genetics), Genome-Wide Association Study
Abstract

Imputation is a computational method based on the principle of haplotype sharing allowing enrichment of genome-wide association study datasets. It depends on the haplotype structure of the population and density of the genotype data. The 1000 Genomes Project led to the generation of imputation reference panels which have been used globally. However, recent studies have shown that population-specific panels provide better enrichment of genome-wide variants. We compared the imputation accuracy using 1000 Genomes phase 3 reference panel and a panel generated from genome-wide data on 407 individuals from Western India (WIP). The concordance of imputed variants was cross-checked with next-generation re-sequencing data on a subset of genomic regions. Further, using the genome-wide data from 1880 individuals, we demonstrate that WIP works better than the 1000 Genomes phase 3 panel and when merged with it, significantly improves the imputation accuracy throughout the minor allele frequency range. We also show that imputation using only South Asian component of the 1000 Genomes phase 3 panel works as good as the merged panel, making it computationally less intensive job. Thus, our study stresses that imputation accuracy using 1000 Genomes phase 3 panel can be further improved by including population-specific reference panels from South Asia.

Published
2017

42. GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians

Author

Sirazul A. Sahariah, Suraj S. Nongmaithem, Caroline H.D. Fall, Swetha Ramachandran, Giriraj R. Chandak, Harsha Chopra, Meera Gandhi, Ghattu V. Krishnaveni, Chittaranjan S. Yajnik, Anand Pandit, Meraj Ahmad, C. V. Joglekar, and Ramesh D. Potdar

Subjects
Adult, Male, 0301 basic medicine, Linkage disequilibrium, India, 030209 endocrinology & metabolism, Genome-wide association study, Single-nucleotide polymorphism, Biology, 01 natural sciences, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, 03 medical and health sciences, 0302 clinical medicine, Asian People, Gene Frequency, Genetics, Humans, Vitamin B12, 0101 mathematics, Allele, Enhancer, Child, Promoter Regions, Genetic, Allele frequency, Molecular Biology, Fucosylation, Alleles, Genetics (clinical), 2. Zero hunger, Association Studies Articles, General Medicine, Middle Aged, Fucosyltransferases, 3. Good health, 010101 applied mathematics, Vitamin B 12, Genetics, Population, 030104 developmental biology, Child, Preschool, 030220 oncology & carcinogenesis, Female, Erratum, Genome-Wide Association Study
Abstract

Vitamin B12 is an important cofactor in one-carbon metabolism whose dysregulation is associated with various clinical conditions. Indians have a high prevalence of B12 deficiency but little is known about the genetic determinants of circulating B12 concentrations in Indians. We performed a genome-wide association study in 1001 healthy participants in the Pune Maternal Nutrition Study (PMNS), replication studies in 3418 individuals from other Indian cohorts and by meta-analysis identified new variants, rs3760775 (P = 1.2 × 10−23) and rs78060698 (P = 8.3 × 10−17) in FUT6 to be associated with circulating B12 concentrations. Although in-silico analysis replicated both variants in Europeans, differences in the effect allele frequency, effect size and the linkage disequilibrium structure of credible set variants with the reported variants suggest population-specific characteristics in this region. We replicated previously reported variants rs602662, rs601338 in FUT2, rs3760776, rs708686 in FUT6, rs34324219 in TCN1 (all P

Published
2017

43. Protocol for the EMPHASIS study; epigenetic mechanisms linking maternal pre-conceptional nutrition and children's health in India and Sub-Saharan Africa

Author

Giriraj R, Chandak, Matt J, Silver, Ayden, Saffari, Karen A, Lillycrop, Smeeta, Shrestha, Sirazul Amin, Sahariah, Chiara, Di Gravio, Gail, Goldberg, Ashutosh Singh, Tomar, Modupeh, Betts, Sara, Sajjadi, Lena, Acolatse, Philip, James, Prachand, Issarapu, Kalyanaraman, Kumaran, Ramesh D, Potdar, Andrew M, Prentice, and Caroline Hd, Fall

Subjects
Article
Abstract

BACKGROUND: Animal studies have shown that nutritional exposures during pregnancy can modify epigenetic marks regulating fetal development and susceptibility to later disease, providing a plausible mechanism to explain the developmental origins of health and disease. Human observational studies have shown that maternal peri-conceptional diet predicts DNA methylation in offspring. However, a causal pathway from maternal diet, through changes in DNA methylation, to later health outcomes has yet to be established. The EMPHASIS study (Epigenetic Mechanisms linking Pre-conceptional nutrition and Health Assessed in India and Sub-Saharan Africa, ISRCTN14266771) will investigate epigenetically mediated links between peri-conceptional nutrition and health-related outcomes in children whose mothers participated in two randomized controlled trials of micronutrient supplementation before and during pregnancy. METHODS: The original trials were the Mumbai Maternal Nutrition Project (MMNP, ISRCTN62811278) in which Indian women were offered a daily snack made from micronutrient-rich foods or low-micronutrient foods (controls), and the Peri-conceptional Multiple Micronutrient Supplementation Trial (PMMST, ISRCTN13687662) in rural Gambia, in which women were offered a daily multiple micronutrient (UNIMMAP) tablet or placebo. In the EMPHASIS study, DNA methylation will be analysed in the children of these women (~1,100 children aged 5-7 y in MMNP and 298 children aged 7-9 y in PMMST). Cohort-specific and cross-cohort effects will be explored. Differences in DNA methylation between allocation groups will be identified using the Illumina Infinium MethylationEPIC array, and by pyrosequencing top hits and selected candidate loci. Associations will be analysed between DNA methylation and health-related phenotypic outcomes, including size at birth, and children’s post-natal growth, body composition, skeletal development, cardio-metabolic risk markers (blood pressure, serum lipids, plasma glucose and insulin) and cognitive function. Pathways analysis will be used to test for enrichment of nutrition-sensitive loci in biological pathways. Causal mechanisms for nutrition-methylation-phenotype associations will be explored using Mendelian Randomization. Associations between methylation unrelated to supplementation and phenotypes will also be analysed. CONCLUSION: The study will increase understanding of the epigenetic mechanisms underpinning the long-term impact of maternal nutrition on offspring health. It will potentially lead to better nutritional interventions for mothers preparing for pregnancy, and to identification of early life biomarkers of later disease risk.

Published
2019

44. The genetic architecture of type 2 diabetes

Author

Clement Ma, Liisa Hakaste, Claes Ladenvall, Massimo Mangino, Lars Lind, Aaron G. Day-Williams, Ryan Poplin, Thomas Schwarzmayr, Annette Peters, Thomas Meitinger, Satish Kumar, Kyong Soo Park, Ching-Yu Cheng, Farook Thameem, Kyle J. Gaulton, Olov Rolandsson, Yossi Farjoun, Neil Robertson, Mauricio O. Carneiro, Mark A. DePristo, Pierre Fontanillas, Ruth J. F. Loos, Heather M. Highland, Vilmantas Giedraitis, Gemma Buck, Fredrik Karpe, Mohammad Kamran Ikram, Alex S. F. Doney, Hae Kyung Im, Eric S. Lander, Johanna Kuusisto, Dorothée Thuillier, Denis Rybin, Jacquelyn Murphy, Benjamin M. Neale, Martina Müller-Nurasyid, Eric R. Gamazon, Johanne Marie Justesen, Tin Aung, Vincent K. L. Lam, John Danesh, Donna M. Lehman, Goo Jun, Marit E. Jørgensen, Christian Herder, Edmund Chan, Pamela J. Hicks, Todd Green, Claudia Langenberg, Yoon Shin Cho, James G. Wilson, Daniel E. Hale, Rector Arya, Giriraj R. Chandak, Juan Fernandez Tajes, Jaakko Tuomilehto, Christopher P. Jenkinson, Anders Rosengren, Torsten Lauritzen, Michael Griswold, Karen L. Mohlke, Amy J. Swift, Alena Stančáková, Christian Fuchsberger, Iksoo Huh, Nikhil Tandon, João Fadista, Christa Meisinger, Gonçalo R. Abecasis, Pål R. Njølstad, Dwaipayan Bharadwaj, Richard M. Watanabe, Shaun Purcell, Veikko Salomaa, Tim D. Spector, Paul W. Franks, Adam E. Locke, Sharon P. Fowler, Panos Deloukas, Reedik Mägi, Solomon K. Musani, Kee Seng Chia, Barbara Thorand, Soo Heon Kwak, Annemari Käräjämäki, Evelin Mihailov, John Blangero, Thomas Wieland, Christian Gieger, E. Shyong Tai, Jianjun Liu, James B. Meigs, Teemu Kuulasmaa, Martin Hrabé de Angelis, Francis S. Collins, Tim M. Strom, Tibor V. Varga, Juyoung Lee, Mark I. McCarthy, Domenico Palli, Jong-Young Lee, Benjamin Glaser, Tasha E. Fingerlin, Stephen O'Rahilly, Andrew T. Hattersley, Gil Atzmon, Manuel A. Rivas, Noël P. Burtt, Ivan Brandslund, Young-Jin Kim, Dorairaj Prabhakaran, Xu Wang, Taylor J. Maxwell, Valeriya Lyssenko, Frank B. Hu, Adolfo Correa, Khalid Shakir, Kathleen A. Jablonski, Yingchang Lu, Wei-Yen Lim, Min Jin Go, William R. Scott, Hanna E. Abboud, Leena Kinnunen, Inês Barroso, Gabriela L. Surdulescu, Peng Chen, Robert Sladek, Marju Orho-Melander, Xueling Sim, Robert A. Scott, Joanna M. M. Howson, Markku Laakso, David Altshuler, Vidya S. Farook, Harald Grallert, Janina S. Ried, Vineeta Agarwala, Philippe Froguel, Nicholas J. Wareham, Tiinamaija Tuomi, Joon Yoon, Heikki A. Koistinen, Toni I. Pollin, Heiner Boeing, Marie Loh, Nicola L. Beer, Joanne E. Curran, Lars Lannfelt, Dorota Pasko, Taesung Park, David Buck, Nir Barzilai, Stephen C. J. Parker, Michael Roden, Bok-Ghee Han, David Aguilar, Timothy Fennell, Sian-Tsung Tan, Gregory P. Wilson, Momoko Horikoshi, Cramer Christensen, Craig L. Hanis, Gilean McVean, Benjamin F. Voight, Wolfgang Rathmann, Jared Maguire, Ashok Kumar, Donald W. Bowden, Michael L. Stitzel, Yongkang Kim, Christine Blancher, Jason Carey, Min-Seok Kwon, Nicholette D. Palmer, Oluf Pedersen, Niels Grarup, Peter S. Chines, Cornelia Huth, James Scott, Torben Hansen, Konstantin Strauch, Erwin P. Bottinger, Andrew D. Morris, Anette P. Gjesing, Erik Ingelsson, Colin N. A. Palmer, Claudia H. T. Tam, Stacey Gabriel, Pablo Cingolani, Beverley Balkau, Michael Boehnke, Peter M. Nilsson, Wing-Yee So, Andrew R. Wood, Lili Milani, Ravindranath Duggirala, Qibin Qi, Mark Walker, Weiping Jia, Mark Seielstad, Narisu Narisu, Tien Yin Wong, Martijn van de Bunt, Anubha Mahajan, Davis J. McCarthy, Ann-Christine Syvänen, Jennifer Kriebel, N. William Rayner, Han Chen, Jinyan Huang, Chiea Chuen Khor, Richard N. Bergman, Shah Ebrahim, Dylan Hodgkiss, Weihua Zhang, Manjinder S. Sandhu, Richard D. Pearson, Juliana C.N. Chan, Rainer Rauramaa, Ralph A. DeFronzo, Andrew Farmer, Yoshihiko Nagai, Allan Linneberg, Herman A. Taylor, Jose C. Florez, Jaspal S. Kooner, Lori L. Bonnycastle, Jeroen R. Huyghe, Leif Groop, Joseph Trakalo, Sobha Puppala, Bong-Jo Kim, Kathleen Stirrups, Kerrin S. Small, Cecilia M. Lindgren, Jennifer E. Below, Heung Man Lee, Inga Prokopenko, Liming Liang, Timothy M. Frayling, Uzma Afzal, Mark J. Daly, Yik Ying Teo, Andrew P. Morris, Phoenix Kwan, Yvonne T. van der Schouw, Cheng Hu, Katharine R. Owen, Alisa K. Manning, Christopher J. Groves, Josée Dupuis, Ryan P. Welch, Loukas Moutsianas, Joshua D. Smith, Tanya M. Teslovich, Robert C. Onofrio, Maggie C.Y. Ng, Peter Donnelly, Tõnu Esko, Matt Neville, Bo Isomaa, Anne U. Jackson, Jette Bork-Jensen, Barry I. Freedman, Yi Chen, Danish Saleheen, Lu Qi, Laura J. Scott, Jasmina Kravic, Paul Elliott, Mette Hollensted, Carmen Navarro, Selyeong Lee, Benjamin Lehne, Thomas Illig, Nancy J. Cox, Jonathan C. Levy, George B. Grant, John C. Chambers, Adam S. Butterworth, Ronald C.W. Ma, Teresa Ferreira, John R. B. Perry, Eleftheria Zeggini, Hyun Min Kang, Loic Yengo, Eric Banks, Jae-Hoon Lee, Anna L. Gloyn, Christopher Hartl, Wei Zhao, Andres Metspalu, Keng-Han Lin, Graeme I. Bell, Jason Flannick, Torben Jørgensen, Thomas W. Blackwell, Heather M. Stringham, Olle Melander, Omri Gottesman, Other departments, British Heart Foundation, Wellcome Trust, Medical Research Council (MRC), Massachusetts Institute of Technology. Department of Biology, Altshuler, David M, Internal Medicine, Perry, John [0000-0001-6483-3771], Butterworth, Adam [0000-0002-6915-9015], Howson, Joanna [0000-0001-7618-0050], Danesh, John [0000-0003-1158-6791], Johnson, Kathleen [0000-0002-6823-3252], O'Rahilly, Stephen [0000-0003-2199-4449], Langenberg, Claudia [0000-0002-5017-7344], Sandhu, Manjinder [0000-0002-2725-142X], Barroso, Ines [0000-0001-5800-4520], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, PROTEIN INTERACTION NETWORKS, SUSCEPTIBILITY LOCI, Genotyping Techniques, General Science & Technology, DNA Mutational Analysis, SEQUENCING ASSOCIATION, 030209 endocrinology & metabolism, Genome-wide association study, Biology, Research Support, N.I.H, 03 medical and health sciences, 0302 clinical medicine, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Genetic predisposition, Journal Article, Humans, Exome, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Non-U.S. Gov't, Exome sequencing, Alleles, Genetic association, Genetics, RISK, Multidisciplinary, HERITABILITY, Research Support, Non-U.S. Gov't, COMPLEX TRAITS, Extramural, Genetic Variation, Genetic architecture, HUMAN-DISEASE, Europe, 030104 developmental biology, Diabetes Mellitus, Type 2, RARE VARIANTS, Sample Size, LOW-FREQUENCY, Imputation (genetics), Common disease-common variant, Genome-Wide Association Study
Abstract

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

Published
2016

45. Candidate genes linking maternal nutrient exposure to offspring health via DNA methylation: a review of existing evidence in humans with specific focus on one-carbon metabolism

Author

Fall Chd, Philip T. James, Prachand Issarapu, Dilip K. Yadav, Smeeta Shrestha, Lovejeet Kaur, Ashutosh Singh Tomar, Sara Sajjadi, Matt J. Silver, Giriraj R. Chandak, Karen A. Lillycrop, Ayden Saffari, and Andrew M. Prentice

Subjects
0301 basic medicine, Candidate gene, Epidemiology, Offspring, growth, Developmental Origins of Health and Disease, Computational biology, Biology, Epigenesis, Genetic, 03 medical and health sciences, Pregnancy, Humans, Epigenetics, Gene, metastable epialleles, DNA methylation, Maternal Nutritional Physiological Phenomena, Nutrients, General Medicine, Epigenome, one-carbon metabolism, Carbon, Diet, fetal programming, 030104 developmental biology, Gene Expression Regulation, cardiometabolic outcomes, Female, candidate genes, Candidate Disease Gene, Genomic imprinting, cognitive development
Abstract

BackgroundMounting evidence suggests that nutritional exposures during pregnancy influence the fetal epigenome, and that these epigenetic changes can persist postnatally, with implications for disease risk across the life course.MethodsWe review human intergenerational studies using a three-part search strategy. Search 1 investigates associations between preconceptional or pregnancy nutritional exposures, focusing on one-carbon metabolism, and offspring DNA methylation. Search 2 considers associations between offspring DNA methylation at genes found in the first search and growth-related, cardiometabolic and cognitive outcomes. Search 3 isolates those studies explicitly linking maternal nutritional exposure to offspring phenotype via DNA methylation. Finally, we compile all candidate genes and regions of interest identified in the searches and describe their genomic locations, annotations and coverage on the Illumina Infinium Methylation beadchip arrays.ResultsWe summarize findings from the 34 studies found in the first search, the 31 studies found in the second search and the eight studies found in the third search. We provide details of all regions of interest within 45 genes captured by this review.ConclusionsMany studies have investigated imprinted genes as priority loci, but with the adoption of microarray-based platforms other candidate genes and gene classes are now emerging. Despite a wealth of information, the current literature is characterized by heterogeneous exposures and outcomes, and mostly comprise observational associations that are frequently underpowered. The synthesis of current knowledge provided by this review identifies research needs on the pathway to developing possible early life interventions to optimize lifelong health.

Published
2018

46. Adult onset hereditary hemochromatosis is associated with a novel recurrent Hemojuvelin (HJV) gene mutation in north Indians

Author

Yogesh Chawla, Gurjeewan Garewal, Manu Jamwal, Barjinderjit Kaur Dhillon, Ajay Duseja, Pankaj Malhotra, Gunjan Chopra, Giriraj R. Chandak, and Reena Das

Subjects
0301 basic medicine, Adult, Male, Heterozygote, Delayed Diagnosis, Mutation, Missense, India, Gene mutation, medicine.disease_cause, Compound heterozygosity, GPI-Linked Proteins, Polymorphism, Single Nucleotide, 03 medical and health sciences, Exon, 0302 clinical medicine, medicine, Humans, Hemochromatosis Protein, Molecular Biology, Hemojuvelin, Genetics, Mutation, business.industry, Homozygote, Cell Biology, Hematology, Sequence Analysis, DNA, Middle Aged, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Hereditary hemochromatosis, Molecular Medicine, Female, HAMP, Hemochromatosis, Siderosis, business
Abstract

Hereditary hemochromatosis (HH) is a rare disorder in Indians and is not associated with the common mutation Cys282Tyr in HFE gene found in Caucasians. Non-HFE HH can be associated with mutations in HJV, HAMP, TFR2 and SLC40A1 genes. Nineteen unrelated north Indian HH patients were detected after screening 258 chronic liver disease patients on the basis of increased transferrin saturation, ferritin levels >1000 ng/L and siderosis by Perl's stain on liver biopsy wherever available. Automated DNA sequencing was performed for the promoters and entire coding exons for HFE, HJV, HAMP, TFR2 and SLC40A1. A novel homozygous mutation at position p.Gly336Ter (c.1006 G>T) in exon 4 in HJV was identified in four adult unrelated patients. We encountered compound heterozygosity for p.Thr217Ile (c.650C>T) and p.His63Asp (c.187C>G) mutation of HFE gene in one patient. Two patients were compound heterozygous for two novel polymorphisms at c.−358 (G>A) and c.−36 (G>A) in 5′UTR of HJV gene. Our study shows a novel HJV gene mutation p.Gly336Ter as a recurrent mutation associated with HH in north Indians. Low index of suspicion, underlying nutritional iron deficiency and protective effect of menstrual blood loss may account for the late clinical presentation of juvenile HH.

Published
2018

47. Life course programming of stress responses in adolescents and young adults in India: Protocol of the Stress Responses in Adolescence and Vulnerability to Adult Non-communicable disease (SRAVANA) Study

Author

Giriraj R. Chandak, Vijay Danivas, Krishnamachari Srinivasan, Clive Osmond, Kalyanaraman Kumaran, Chittaranjan S. Yajnik, Samuel C Karat, Ghattu V. Krishnaveni, Murali Krishna, Dattatray S. Bhat, Caroline H.D. Fall, J Suguna Shanthi, Alexander Jones, Mary Barker, Sarah H Kehoe, and Sirazul A. Sahariah

Subjects
Medicine (miscellaneous), India, 030209 endocrinology & metabolism, General Biochemistry, Genetics and Molecular Biology, TSST, 03 medical and health sciences, Study Protocol, 0302 clinical medicine, Trier social stress test, Medicine, 030212 general & internal medicine, adolescents, Young adult, Risk factor, non-communicable disease, business.industry, Stressor, Repeated measures design, Articles, stress response, Non-communicable disease, medicine.disease, 3. Good health, Cohort, Life course approach, business, Clinical psychology, maternal nutrition
Abstract

Background:Early life nutrition may affect individuals’ susceptibility to adult non-communicable diseases (NCD). Psychological stress is a well-recognised NCD risk factor. Recent evidence suggests that impaired foetal nutrition alters neuro-endocrine pathways, and hypothalamic-pituitary-adrenal axis feedback systems, resulting in abnormal stress responses, and NCD risk. This study aims to examine adolescent cortisol and cardiovascular stress responses in relation to maternal nutrition and contemporaneous NCD risk markers.Methods: The study sample will be drawn from three well-established birth cohorts in India; the Parthenon cohort, Mysore (N=550, age~20y), the SARAS KIDS prenatal intervention cohort, Mumbai (N=300, age~10-12y) and the Pune Rural Intervention in Young Adults/ PRIYA cohort, Pune (N=100, age~22y). We will perform the ‘Trier Social Stress Test (TSST)’, a well-accepted stress-test module which involves participants performing 5-minutes each of public speaking and mental arithmetic tasks in front of unfamiliar ‘judges’ (stressor). Repeated measures of salivary cortisol and autonomic cardiovascular outcomes relative to the stressor will be assessed. Measures of psychological stress, cognitive function, blood pressure, glucose-insulin metabolism and depression will be carried out. Mechanistic studies including DNA methylation in gluco-corticoid receptor (NR3C1) and11β-HSD2gene loci and neuroimaging will be carried out in a subsample. Qualitative interviews and focus group discussions in a subsample of the Parthenon cohort will explore the perception of stress and stressors among the youth.We will convert repeated measures into time-weighted averages before analysis. We will carry out multivariable regression analysis to test the associations. We will further refine the analyses using the mixed-model regression and conditional analyses for the association with repeated measures. Ethics and dissemination:This study has been approved by the research ethics committee of CSI Holdsworth Memorial Hospital, Mysore. The findings will be disseminated locally and at international meetings, and reports will be submitted to open access peer reviewed journals.

Published
2018

48. Vitamin B

Author

Dilip K, Yadav, Smeeta, Shrestha, Karen A, Lillycrop, Charu V, Joglekar, Hong, Pan, Joanna D, Holbrook, Caroline Hd, Fall, Chittaranjan S, Yajnik, and Giriraj R, Chandak

Subjects
Epigenomics, Male, MicroRNAs, Vitamin B 12, Diabetes Mellitus, Type 2, Dietary Supplements, Vitamin B Complex, Humans, Female, DNA Methylation, Child
Abstract

To investigate the effect of BWe performed Infinium HumanMethylation450 BeadChip (Zymo Research, CA, USA) assay in children supplemented with BWe noted significant methylation changes postsupplementation in BB

Published
2017

49. Intrauterine Programming of Diabetes and Adiposity

Author

Ashutosh Singh Tomar, Chittaranjan S. Yajnik, Giriraj R. Chandak, Suraj S. Nongmaithem, Smeeta Shrestha, and Divya Sri Priyanka Tallapragada

Subjects
medicine.medical_specialty, Pathology, Disease, Epigenesis, Genetic, Fetal Development, Missing heritability problem, Environmental health, Diabetes mellitus, Epidemiology, Mendelian randomization, Prevalence, medicine, Humans, Genetic Predisposition to Disease, Obesity, Adiposity, business.industry, Maternal Nutritional Physiological Phenomena, General Medicine, Heritability, medicine.disease, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Female, Disease prevention, Animal studies, Insulin Resistance, business
Abstract

The prevalence of diabetes and adiposity has increased at an alarming rate and together they contribute to the rise in morbidity and mortality worldwide. Genetic studies till date have succeeded in explaining only a proportion of heritability, while a major component remains unexplained. Early life determinants of future risk of these diseases are likely contributors to the missing heritability and thus have a significant potential in disease prevention. Epidemiological and animal studies show the importance of intrauterine and early postnatal environment in programming of the fetus to adverse metabolic outcomes and support the notion of Developmental Origins of Health and Disease (DOHaD). Emerging evidence highlights the role of epigenetic mechanisms in mediating effects of environmental exposures, which in certain instances may exhibit intergenerational transmission even in the absence of exposure. In this article, we will discuss the complexity of diabetes and increased adiposity and mechanisms of programming of these adverse metabolic conditions.

Published
2015

50. Identification of a functional enhancer variant within the chronic pancreatitis‐associated SPINK1 c.101A>G (p.Asn34Ser)‐containing haplotype

Author

Giriraj R. Chandak, David Neil Cooper, Emmanuelle Masson, Sumit Paliwal, Emmanuelle Génin, Hao Wu, Claude Férec, Prachand Issarapu, Wen-Bin Zou, Seema Bhaskar, Zhao-Shen Li, Arnaud Boulling, Jian-Min Chen, Zhuan Liao, INSERM U1078, and Université de Brest (UBO)

Subjects
0301 basic medicine, Linkage disequilibrium, Population, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 03 medical and health sciences, Transactivation, 0302 clinical medicine, Pancreatitis, Chronic, Genetics, SNP, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Hepatocyte Nuclear Factor 1-alpha, Enhancer, education, Promoter Regions, Genetic, Genetics (clinical), Phylogeny, education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, Binding Sites, Phylogenetic tree, Haplotype, 030104 developmental biology, Haplotypes, Trypsin Inhibitor, Kazal Pancreatic, 030211 gastroenterology & hepatology
Abstract

The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser) variant (also known as rs17107315:T>C) represents the most important heritable risk factor for idiopathic chronic pancreatitis identified to date. The causal variant contained within this risk haplotype has however remained stubbornly elusive. Herein, we set out to resolve this enigma by employing a hypothesis-driven approach. First, we searched for variants in strong linkage disequilibrium (LD) with rs17107315:T>C using HaploReg v4.1. Second, we identified two candidate SNPs by visual inspection of sequences spanning all 25 SNPs found to be in LD with rs17107315:T>C, guided by prior knowledge of pancreas-specific transcription factors and their cognate binding sites. Third, employing a novel cis-regulatory module (CRM)-guided approach to further filter the two candidate SNPs yielded a solitary candidate causal variant. Finally, combining data from phylogenetic conservation and chromatin accessibility, cotransfection transactivation experiments, and population genetic studies, we suggest that rs142703147:C>A, which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A−PTF1L CRM located ∼4 kb upstream of the SPINK1 promoter, contributes to the aforementioned chronic pancreatitis risk haplotype. Further studies are required not only to improve the characterization of this functional SNP but also to identify other functional components that might contribute to this high-risk haplotype.

Published
2017

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