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Genetics and epigenetics

Identification of a 1p21 independent functional variant for abdominal obesity



Aiming to uncover the genetic basis of abdominal obesity, we performed a genome-wide association study (GWAS) meta-analysis of trunk fat mass adjusted by trunk lean mass (TFMadj) and followed by a series of functional investigations.


A total of 11,569 subjects from six samples were included into the GWAS meta-analysis.


Meta-analysis was performed by a weighted fixed-effects model. In silico replication analysis was performed in the UK-Biobank (UKB) sample (N = 331,093) and in the GIANT study (N up to 110,204). Cis-expression QTL (cis-eQTL) analysis, dual-luciferase reporter assay and electrophoresis mobility shift assay (EMSA) were conducted to examine the functional relevance of the identified SNPs. At last, differential gene expression analysis (DGEA) was performed.


We identified an independent SNP rs12409479 at 1p21 (MAF = 0.07, p = 7.26 × 10−10), whose association was replicated by the analysis of TFM in the UKB sample (one-sided p = 3.39 × 10−3), and was cross-validated by the analyses of BMI (one-sided p = 0.03) and WHRadj (one-sided p = 0.04) in the GIANT study. Cis-eQTL analysis demonstrated that allele A at rs12409479 was positively associated with PTBP2 expression level in subcutaneous adipose tissue (N = 385, p = 4.15 × 10−3). Dual-luciferase reporter assay showed that the region repressed PTBP2 gene expression by downregulating PTBP2 promoter activity (p < 0.001), and allele A at rs12409479 induced higher luciferase activity than allele G did (p = 4.15 × 10−3). EMSA experiment implied that allele A was more capable of binding to unknown transcription factors than allele G. Lastly, DGEA showed that the level of PTBP2 expression was higher in individuals with obesity than in individuals without obesity (N = 20 and 11, p = 0.04 and 9.22 × 10−3), suggesting a regulatory role in obesity development.


Taken together, we hypothesize a regulating path from rs12409479 to trunk fat mass development through its allelic specific regulation of PTBP2 gene expression, thus providing some novel insight into the genetic basis of abdominal obesity.

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We are grateful to Loula M. Burton at the Tulane University for editing the manuscript. We appreciate all the volunteers who participated into this study. We are grateful to the GIANT consortium, the UK-Biobank, and Dr. Neale’s lab researchers for releasing large-scale summary association results for replication. This study was partially supported by the National Natural Science Foundation of China (31771417 and 31501026 to Y-FP, 31571291 to LZ), the Natural Science Foundation of Jiangsu Province of China (BK20150323 to Y-FP), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education (to Y-FP), the NIH (R01 AR069055, U19 AG055373, R01 MH104680, R01 AR059781 and P20 GM109036 to H-WD), the Edward G. Schlieder Endowment (to H-WD), the startup funding project of Soochow University (Q413900214 to LZ and Q413900114 to Y-FP) and a Project of the Priority Academic Program Development of Jiangsu Higher Education Institutions. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL-64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Funding support for the Framingham Whole Body and Regional Dual X-ray Absorptiometry (DXA) dataset was provided by NIH grants R01 AR/AG 41398. The datasets used for the analyses described in this manuscript were obtained from dbGaP ( through dbGaP accession phs000342.v14.p10. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and the US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. This manuscript was not prepared in collaboration with investigators of the WHI, has not been reviewed and/or approved by the Women’s Health Initiative (WHI), and does not necessarily reflect the opinions of the WHI investigators or the NHLBI. Funding for WHI SHARe genotyping was provided by NHLBI contractN02-HL-64278.The datasets used for the analyses described in this manuscript were obtained from dbGaP at through dbGaP accession phs000200.v10.p3.

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Correspondence to Hong-Wen Deng or Lei Zhang.

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The authors declare that they have no conflict of interest.

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Samples used in this study are from multiple research and/or clinical centers. All samples were approved by the respective institutional ethics review boards, and all participants signed informed consent documents before being enrolled into the study.

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Liu, L., Pei, YF., Liu, TL. et al. Identification of a 1p21 independent functional variant for abdominal obesity. Int J Obes 43, 2480–2490 (2019).

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