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Two novel pleiotropic loci associated with osteoporosis and abdominal obesity

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Abstract

Aiming to uncover a shared genetic basis of abdominal obesity and osteoporosis, we performed a bivariate GWAS meta-analysis of femoral neck BMD (FNK-BMD) and trunk fat mass adjusted by trunk lean mass (TFMadj) in 11,496 subjects from 6 samples, followed by in silico replication in the large-scale UK Biobank (UKB) cohort. A series of functional investigations were conducted on the identified variants. Bivariate GWAS meta-analysis identified two novel pleiotropic loci 12q15 (lead SNP rs73134637, p = 3.45 × 10–7) and 10p14 (lead SNP rs2892347, p = 2.63 × 10–7) that were suggestively associated and that were replicated in the analyses of related traits in the UKB sample (osteoporosis p = 0.06 and 0.02, BMI p = 0.03 and 4.61 × 10–3, N up to 499,520). Cis-eQTL analysis demonstrated that allele C at rs73134637 was positively associated with IFNG expression in whole blood (N = 369, p = 0.04), and allele A at rs11254759 (10p14, p = 9.49 × 10–7) was negatively associated with PRKCQ expression in visceral adipose tissue (N = 313, p = 0.04) and in lymphocytes (N = 117, p = 0.03). As a proof-of-principle experiment, the function of rs11254759, which is 235 kb 5′-upstream from PRKCQ gene, was investigated by the dual-luciferase reporter assay, which clearly showed that the haplotype carrying rs11254759 regulated PRKCQ expression by upregulating PRKCQ promoter activity (p = 4.60 × 10–7) in an allelic specific manner. Mouse model analysis showed that heterozygous PRKCQ deficient mice presented decreased fat mass compared to wild-type control mice (p = 3.30 × 10–3). Mendelian randomization analysis demonstrated that both FNK-BMD and TFMadj were causally associated with fracture risk (p = 1.26 × 10–23 and 1.18 × 10–11). Our findings may provide useful insights into the genetic association between osteoporosis and abdominal obesity.

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Acknowledgements

We appreciate all the volunteers who participated in this study. We are grateful to the UK Biobank for releasing large-scale summary association results for replication. We are grateful to Loula M Burton at the Tulane University for editing the manuscript. Lei Zhang and Yu-Fang Pei are partially supported by the national natural science foundation of China (31571291, 31771417 and 31501026) and a project of the priority academic program development (PAPD) of Jiangsu higher education institutions. Rong Hai is partially supported by the Inner Mongolia Autonomous Region Medical Health Science & Technology Research Program (201702180). Hui Shen and Hong-Wen Deng are partially supported by the National Institutes of Health (R01AR059781, P20GM109036, R01MH107354, R01MH104680, R01GM109068, R01AR069055, U19AG055373, R01DK115679), the Edward G. Schlieder Endowment and the Drs. W. C. Tsai and P. T. Kung Professorship in Biostatistics from Tulane University. The numerical calculations in this paper have been done on the supercomputing system of the National Supercomputing Center in Changsha. 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 (https://www.ncbi.nlm.nih.gov/sites/entrez?db=gap) through dbGaP accession phs000342.v14.p10. The WHI (Women’s Health Initiative) 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 WHI, and does not necessarily reflect the opinions of the WHI investigators or the NHLBI. Funding for WHI SHARe genotyping was provided by NHLBI contract N02-HL-64278. The datasets used for the analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession phs000200.v10.p3.

Funding

Lei Zhang and Yu-Fang Pei are partially supported by the national natural science foundation of China (31571291, 31771417 and 31501026) and a project of the priority academic program development (PAPD) of Jiangsu higher education institutions. Rong Hai is partially supported by the Inner Mongolia Autonomous region medical health science & technology research program (201702180). Hui Shen and Hong-Wen Deng are partially supported by the National Institutes of Health (R01AR059781, P20GM109036, R01MH107354, R01MH104680, R01GM109068, R01AR069055, U19AG055373, R01DK115679), the Edward G. Schlieder Endowment and the Drs. W. C. Tsai and P. T. Kung Professorship in Biostatistics from Tulane University.

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Authors

Contributions

LZ designed the study. LZ and HWD collected the data. YFP and LZ analyzed the data. LL, XLY, HZ and RH performed the literature search. YFP, LL, LZ interpreted the data. LZ and LL generated the figures. LL drafted the early version of the manuscript. LZ, HWD, XTW, GJF, HS, QT, ZJZ, JL and HPP revised the manuscript. LZ, HWD and YFP supervised the study. All authors were involved in writing the paper and had final approval of the submitted and published versions.

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Correspondence to Hong-Wen Deng, Yu-Fang Pei or Lei Zhang.

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

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All samples were approved by the respective institutional ethics review boards.

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Informed consent was obtained from all individual participants included in the study.

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All participants signed informed consent regarding publishing their data.

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The GWAS summary statistics will be publicly available.

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All computer software are publicly available.

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Hong-Wen Deng, Yu-Fang Pei and Lei Zhang have jointly supervised this study.

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Liu, L., Yang, XL., Zhang, H. et al. Two novel pleiotropic loci associated with osteoporosis and abdominal obesity. Hum Genet 139, 1023–1035 (2020). https://doi.org/10.1007/s00439-020-02155-1

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