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Multifaceted genome-wide study identifies novel regulatory loci for body mass index in Indians

Anil K Giri, Gauri Prasad, Khushdeep Bandesh, Vaisak Parekatt, Anubha Mahajan, Priyanka Banerjee, Yasmeen Kauser, Shraddha Chakraborty, Donaka Rajashekar, INDICO, Abhay Sharma, Sandeep Kumar Mathur, Analabha Basu, Mark I McCarthy, Nikhil Tandon, View ORCID ProfileDwaipayan Bharadwaj
doi: https://doi.org/10.1101/670521
Anil K Giri
1Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi - 110020, India
2Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi - 110020, India
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Gauri Prasad
1Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi - 110020, India
2Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi - 110020, India
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Khushdeep Bandesh
1Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi - 110020, India
2Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi - 110020, India
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Vaisak Parekatt
1Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi - 110020, India
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Anubha Mahajan
3Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
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Priyanka Banerjee
1Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi - 110020, India
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Yasmeen Kauser
1Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi - 110020, India
2Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi - 110020, India
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Shraddha Chakraborty
1Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi - 110020, India
2Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi - 110020, India
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Donaka Rajashekar
1Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi - 110020, India
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Abhay Sharma
1Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi - 110020, India
2Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi - 110020, India
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Sandeep Kumar Mathur
4Department of Endocrinology, S.M.S. Medical College, Jaipur, Rajasthan, India
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Analabha Basu
5National Institute of Biomedical Genomics, P.O.: Netaji Subhas Sanatorium, Kalyani- 741251, West Bengal, India
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Mark I McCarthy
3Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
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Nikhil Tandon
6Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi - 110029, India
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  • For correspondence: db@jnu.ac.in db@mail.jnu.ac.in nikhil_tandon@hotmail.com
Dwaipayan Bharadwaj
2Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi - 110020, India
7Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi - 110067, India
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  • ORCID record for Dwaipayan Bharadwaj
  • For correspondence: db@jnu.ac.in db@mail.jnu.ac.in nikhil_tandon@hotmail.com
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Abstract

Obesity, a risk factor for various human diseases originates through complex interactions between genes and prevailing environment that varies across populations. Indians exhibit a unique obesity phenotype likely attributed by specific gene pool and environmental factors. Here, we present genome-wide association study (GWAS) of 7,259 Indians to understand the genetic architecture of body mass index (BMI) in the population. Our study revealed novel association of variants in BAI3 (rs6913677) and SLC22A11 (rs2078267) at GWAS significance, and of ZNF45 (rs8100011) with near GWAS significance. As genetic loci may dictate the phenotype through modulation of epigenetic processes, we overlapped discovered genetic signatures with DNA methylation patterns of 236 Indian individuals, and analyzed expression of the candidate genes using publicly available data. The variants in BAI3 and SLC22A11 were found to dictate methylation patterns at unique CpGs harboring critical cis- regulatory elements. Further, BAI3, SLC22A11 and ZNF45 variants were found to overlie repressive chromatin, active enhancer, and active chromatin regions, in that order, in human subcutaneous adipose tissue in ENCODE database. Besides, the identified genomic regions represented potential binding sites for key transcription factors implicated in obesity and/or metabolic disorders. Interestingly, rs8100011 (ZNF45) acted as a robust cis-expression quantitative trait locus (cis-eQTL) in subcutaneous adipose tissue in GTEx portal, and ZNF45 gene expression showed an inverse correlation with BMI in skeletal muscle of Indian subjects. Further, gene-based GWAS analysis revealed CPS1 and UPP2 as additional leads regulating BMI in Indians. Our study decodes potential genomic mechanisms underlying obesity phenotype in Indians.

Footnotes

  • ↵& Membership of INDICO consortium has been listed in acknowledgements section

  • Conflicts of interest There was no conflict of interest between authors

  • Financial support This work was supported by Council of Scientific and Industrial Research [CSIR], Government of India through Centre for Cardiovascular and Metabolic Disease Research [CARDIOMED] project [Grant No: BSC0122-(12)] & Department of Biotechnology (DBT), Government of India through BIOCHILD grant given to CSIR-Institute of Genomics and Integrative Biology, New Delhi, India. This study was also partially funded by Department of Science & Technology, Government of India through PURSE II CDST/SR/PURSE PHASE II/11 provided to Jawaharlal Nehru University, New Delhi, India. Part of this work was conducted using the UK Biobank Resource under Application Number 9161.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 13, 2019.
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Multifaceted genome-wide study identifies novel regulatory loci for body mass index in Indians
Anil K Giri, Gauri Prasad, Khushdeep Bandesh, Vaisak Parekatt, Anubha Mahajan, Priyanka Banerjee, Yasmeen Kauser, Shraddha Chakraborty, Donaka Rajashekar, INDICO, Abhay Sharma, Sandeep Kumar Mathur, Analabha Basu, Mark I McCarthy, Nikhil Tandon, Dwaipayan Bharadwaj
bioRxiv 670521; doi: https://doi.org/10.1101/670521
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Multifaceted genome-wide study identifies novel regulatory loci for body mass index in Indians
Anil K Giri, Gauri Prasad, Khushdeep Bandesh, Vaisak Parekatt, Anubha Mahajan, Priyanka Banerjee, Yasmeen Kauser, Shraddha Chakraborty, Donaka Rajashekar, INDICO, Abhay Sharma, Sandeep Kumar Mathur, Analabha Basu, Mark I McCarthy, Nikhil Tandon, Dwaipayan Bharadwaj
bioRxiv 670521; doi: https://doi.org/10.1101/670521

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