Abstract
Lipids foster energy production and their altered levels have been coupled with metabolic ailments. Indians feature high prevalence of metabolic diseases, yet uncharacterized for genes regulating lipid homeostasis. We performed first GWAS for quantitative lipids (total cholesterol, LDL, HDL, and triglycerides) exclusively in 5271 Indians. Further to corroborate our genetic findings, we investigated DNA methylation marks in peripheral blood in Indians at the identified loci (N = 233) and retrieved gene regulatory features from public domains. Recurrent GWAS loci—CELSR2, CETP, LPL, ZNF259, and BUD13 cropped up as lead signals in Indians, reflecting their universal applicability. Besides established variants, we found certain unreported variants at sub-genome-wide level—QKI, REEP3, TMCC2, FAM129C, FAM241B, and LOC100506207. These variants though failed to attain GWAS significance in Indians, but largely turned out to be active CpG sites in human subcutaneous adipose tissue and showed robust association to two or more lipid traits. Of which, QKI variants showed significant association to all four lipid traits and their designated region was observed to be a key gene regulatory segment denoting active transcription particularly in human subcutaneous adipose tissue. Both established and novel loci were observed to be significantly associated with altered DNA methylation in Indians for specific CpGs that resided in key regulatory elements. Further, gene-based association analysis pinpointed novel GWAS loci—LINC01340 and IQCJ-SCHIP1 for TC; IFT27, IFT88, and LINC02141 for HDL; and TEX26 for TG. Present study ascertains universality of selected known genes and also identifies certain novel loci for lipids in Indians by integrating data from various levels of gene regulation.
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Acknowledgements
The authors thank all study participants. We acknowledge the support and participation of members of the INDICO consortium in data generation. We also thank GLGC study for summary statistics for meta-analysis. KB acknowledges CSIR for Senior Research Fellowship (CSIR-SRF). GP and AKG acknowledge UGC for Senior Research Fellowship (UGC-SRF).
Funding
This work was supported by the Council of Scientific and Industrial Research [CSIR], Government of India through Centre for Cardiovascular and Metabolic Disease Research [CARDIOMED] project [Grant No: BSC0122-(8)]. This work was also funded by the Department of Science and Technology-PURSE-II (DST/SR/PURSE Phase II/11) given to Jawaharlal Nehru University, New Delhi, India.
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KB wrote the final version of manuscript. KB and GP researched the data, interpreted the results and drafted the manuscript. KB, GP, AKG, YK, and MU generated the data. AKG performed whole genome DNA methylation study in Indians. AB supervised the statistical analysis and critically reviewed the manuscript. NT provided intellectual inputs. DB is guarantor of work who conceived, supervised, obtained financial support, and oversaw the entire study.
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Bandesh, K., Prasad, G., Giri, A.K. et al. Genome-wide association study of blood lipids in Indians confirms universality of established variants. J Hum Genet 64, 573–587 (2019). https://doi.org/10.1038/s10038-019-0591-7
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DOI: https://doi.org/10.1038/s10038-019-0591-7
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