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Multifaceted genome-wide study identifies novel regulatory loci in SLC22A11 and ZNF45 for body mass index in Indians

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Abstract

Obesity, a risk factor for multiple diseases (e.g. diabetes, hypertension, cancers) originates through complex interactions between genes and prevailing environment (food habit and lifestyle) that varies across populations. Indians exhibit a unique obesity phenotype with high abdominal adiposity for a given body weight compared to matched white populations suggesting presence of population-specific genetic and environmental factors influencing obesity. However, Indian population-specific genetic contributors for obesity have not been explored yet. Therefore, to identify potential genetic contributors, we performed a two-staged genome-wide association study (GWAS) for body mass index (BMI), a common measure to evaluate obesity in 5973 Indian adults and the lead findings were further replicated in 1286 Indian adolescents. Our study revealed novel association of variants—rs6913677 in BAI3 gene (p = 1.08 × 10−8) and rs2078267 in SLC22A11 gene (p = 4.62 × 10−8) at GWAS significance, and of rs8100011 in ZNF45 gene (p = 1.04 × 10−7) with near GWAS significance. As genetic loci may dictate the phenotype through modulation of epigenetic processes, we overlapped genetic data of identified signals with their DNA methylation patterns in 236 Indian individuals and performed methylation quantitative trait loci (meth-QTL) analysis. Further, functional roles of discovered variants and underlying genes were speculated using publicly available gene regulatory databases (ENCODE, JASPAR, GeneHancer, GTEx). The identified variants in BAI3 and SLC22A11 genes were found to dictate methylation patterns at unique CpGs harboring critical cis-regulatory elements. Further, BAI3, SLC22A11 and ZNF45 variants were located in repressive chromatin, active enhancer, and active chromatin regions, respectively, in human subcutaneous adipose tissue in ENCODE database. Additionally, these genomic regions represented potential binding sites for key transcription factors implicated in obesity and/or metabolic disorders. Interestingly, GTEx portal identify rs8100011 as a robust cis-expression quantitative trait locus (cis-eQTL) in subcutaneous adipose tissue (p = 1.6 × 10−7), and ZNF45 gene expression in skeletal muscle of Indian subjects showed an inverse correlation with BMI indicating its possible role in obesity. In conclusion, our study discovered 3 novel population-specific functional genetic variants (rs6913677, rs2078267, rs8100011) in 2 novel (SLC22A11 and ZNF45) and 1 earlier reported gene (BAI3) for BMI in Indians. Our study decodes key genomic loci underlying obesity phenotype in Indians that may serve as prospective drug targets in future.

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Acknowledgements

The authors are greatly thankful to all the study participants. We acknowledge the support and participation of members of the INDICO consortium in data generation. We thank Prof. Mark I McCarthy for providing data for South Asian subjects of United Kingdom Biobank (UKBB) and Prof. Pawan Dhar (School of Biotechnology, Jawaharlal Nehru University, India) for critical evaluation of the manuscript. GP and AKG acknowledge University Grants Commission (UGC), Government of India for Senior Research Fellowship. KB acknowledges Council of Scientific and Industrial Research (CSIR), Government of India for Senior Research Fellowship. Members of INDICO: Viswanathan Mohan, Saurabh Ghosh, Abhay Sharma, Rubina Tabassum, Ganesh Chauhan, Anubha Mahajan, Om Prakash Dwivedi, Lakshmi Ramakrishnan, Radha Venkatesan, M. Chidambaram, D. Prabhakaran, K. S. Reddy, Monisha Banerjee, Madhukar Saxena, Sandeep Kumar Mathur, Anil Bhansali, Viral Shah, S. V. Madhu, R. K. Marwaha, Pradeep Venkatesh, S. K. Aggarwal, Shantanu Sengupta, Sreenivas Chavali, Amitabh Sharma, Analabha Basu, Khushdeep Bandesh, Anil K. Giri, Shraddha Chakraborty, Yasmeen Kauser, B. Abitha, Aditya Undru, Donaka Rajashekar, Vaisak Parekatt, Suki Roy, Anjali Singh, Priyanka Banerjee, Gauri Prasad, Punam Jha, Nikhil Tandon and Dwaipayan Bharadwaj (Coordinator).

Funding

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)] and 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 and 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.

Author information

Author notes

  1. Anil K. Giri, Gauri Prasad and Khushdeep Bandesh contributed equally to this study.

Authors and Affiliations

  1. Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India

    Anil K. Giri, Gauri Prasad, Khushdeep Bandesh, Vaisak Parekatt, Priyanka Banerjee, Yasmeen Kauser, Shraddha Chakraborty, Donaka Rajashekar & Abhay Sharma

  2. Academy of Scientific and Innovative Research, CSIR-Institute of Genomics and Integrative Biology Campus, New Delhi, India

    Anil K. Giri, Gauri Prasad, Khushdeep Bandesh, Yasmeen Kauser, Shraddha Chakraborty, Abhay Sharma & Dwaipayan Bharadwaj

  3. Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK

    Anubha Mahajan & Mark I. McCarthy

  4. Department of Endocrinology, Sawai Man Singh Medical College, Jaipur, Rajasthan, India

    Sandeep Kumar Mathur

  5. National Institute of Biomedical Genomics, Kalyani, West Bengal, India

    Analabha Basu

  6. Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

    Nikhil Tandon

  7. Systems Genomics Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India

    Dwaipayan Bharadwaj

Authors
  1. Anil K. Giri
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  2. Gauri Prasad
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Consortia

INDICO

  • Viswanathan Mohan
  • , Saurabh Ghosh
  • , Abhay Sharma
  • , Rubina Tabassum
  • , Ganesh Chauhan
  • , Anubha Mahajan
  • , Om Prakash Dwivedi
  • , Lakshmi Ramakrishnan
  • , Radha Venkatesan
  • , M. Chidambaram
  • , D. Prabhakaran
  • , K. S. Reddy
  • , Monisha Banerjee
  • , Madhukar Saxena
  • , Sandeep Mathur
  • , Anil Bhansali
  • , Viral Shah
  • , S. V. Madhu
  • , R. K. Marwaha
  • , Pradeep Venkatesh
  • , S. K. Aggarwal
  • , Shantanu Sengupta
  • , Sreenivas Chavali
  • , Amitabh Sharma
  • , Analabha Basu
  • , Khushdeep Bandesh
  • , Anil K. Giri
  • , Shraddha Chakraborty
  • , Yasmeen Kauser
  • , B. Abitha
  • , Aditya Undru
  • , Donaka Rajashekar
  • , Vaisak Parekatt
  • , Suki Roy
  • , Anjali Singh
  • , Priyanka Banerjee
  • , Gauri Prasad
  • , Punam Jha
  • , Nikhil Tandon
  •  & Dwaipayan Bharadwaj

Contributions

AKG and GP: assembled and analyzed data; contributed to discussions and wrote the manuscript; KB: provided intellectual inputs and critically reviewed the manuscript; AKG, GP, KB, VP, PB, YK, SC, DR, and INDICO: helped in sample preparation and data generation; AM and AB: helped in statistical analysis; AM, AS, SKM, AB, MIM and NT: critically reviewed the manuscript; DB: is the guarantor of this work who conceived, supervised, obtained financial support and oversaw the entire study.

Corresponding authors

Correspondence to Nikhil Tandon or Dwaipayan Bharadwaj.

Ethics declarations

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical approval

The study was approved by Human Ethics Committees of All India Institute of Medical Sciences, New Delhi and CSIR-Institute of Genomics and Integrative Biology, New Delhi, India and was conducted in accordance with the principles of Helsinki Declarations.

Informed consent

The adult participants were informed about objectives of study and written consents were taken from all of them. For adolescent study population, prior official permission from school authorities, informed written consent from parents and verbal consent from participants themselves were obtained before their participation in the study.

Additional information

Communicated by Stefan Hohmann.

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Membership of INDICO consortium has been listed in acknowledgements section.

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Giri, A.K., Prasad, G., Bandesh, K. et al. Multifaceted genome-wide study identifies novel regulatory loci in SLC22A11 and ZNF45 for body mass index in Indians. Mol Genet Genomics 295, 1013–1026 (2020). https://doi.org/10.1007/s00438-020-01678-6

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