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Sex differences of the shared genetic landscapes between type 2 diabetes and peripheral artery disease in East Asians and Europeans

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Abstract

Type 2 diabetes (T2D) is a critical risk factor for peripheral artery disease (PAD). However, the sex differences in genetic basis, causality, and underlying mechanisms of the two diseases are still unclear. Using sex-stratified and ethnic-based GWAS summary, we explored the genetic correlation and causal relationship between T2D and PAD in both ethnicities and sexes by linkage disequilibrium score regression, LAVA and six Mendelian Randomization approaches. We observed stronger genetic correlations between T2D and PAD in females than males in East Asians and Europeans. East Asian females exhibit higher causal effects of T2D on PAD than males. The gene-level analysis found KCNJ11 and ANK1 genes associated with the cross-trait of T2D and PAD in both sexes. Our study provides genetic evidence for the sex difference of genetic correlations and causal relationships between PAD and T2D, indicating the importance of using sex-specific strategies for monitoring PAD in T2D patients.

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Data availability

Summary statistics are publicly available at https://blog.nus.edu.sg/agen/summary-statistics/t2d-2020/ and http://jenger.riken.jp/en/. Codes and software used in the study are available in the following links: LDSC: https://github.com/bulik/ldsc; LAVA: https://ctg.cncr.nl/software/Lava; TwoSampleMR: https://mrcieu.github.io/TwoSampleMR/; CAUSE: https://jean997.github.io/cause/index.html; GSMR: http://cnsgenomics.com/software/gsmr/; MR-PRESSO: https://github.com/rondolab/MR-PRESSO; MAGMA: https://ctg.cncr.nl/software/magma; SMR: https://cnsgenomics.com/software/smr/; MTAG: https://github.com/JonJala/mtag

Abbreviations

SNPs:

Single nucleotide polymorphisms

GWAS:

Genome-wide association studies

AGEN:

Asian Genetic Epidemiology Network

BBJ:

BioBank Japan

UKB:

UK Biobank

T2D:

Type 2 diabetes

PAD:

Peripheral artery disease

LDSC:

Linkage disequilibrium score regression

MR:

Mendelian randomization

CAUSE:

Causal analysis using summary effect estimates

GSMR:

Generalized summary-data-based Mendelian randomization

IVW:

Inverse variance weighted

MAGMA:

Multi-marker analysis of genomic annotation

MTAG:

Genome-wide association summary statistics

SMR:

Summary data-based Mendelian randomization analysis

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Acknowledgements

The authors thank the UKB, BBJ and AGEN project for making data available. H.Zhao designed the study. Z.L and H.Zhang conducted analyses, with assistance from Y.Y, H.Zhao. Z.L, H.Zhang, Y.Y and H.Zhao wrote the manuscript. H.Zhao supervised the study. All authors contributed to the final revision of the paper.

Funding

The work was funded by the Natural Science Foundation of China (81801132, and 81971190; HY.Zhao, Sun Yat-sen Memorial Hospital; 61772566, 62041209, and U1611261).

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Authors and Affiliations

  1. Department of Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangzhou, China

    Zhiya Lu & Huiying Zhao

  2. School of Data and Computer Science, Sun Yat-sen University, Guangzhou, China

    Haoyang Zhang

  3. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia

    Yuanhao Yang

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  1. Zhiya Lu
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Contributions

The authors thank the UKB, BBJ and AGEN project for making data available.H.Zhao designed the study. Z.L and H.Zhang conducted analyses, with assistance from Y.Y, H.Zhao. Z.L, H.Zhang, Y.Y and H.Zhao wrote the manuscript. H.Zhao supervised the study. All authors contributed to the final revision of the paper.

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Correspondence to Huiying Zhao.

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Lu, Z., Zhang, H., Yang, Y. et al. Sex differences of the shared genetic landscapes between type 2 diabetes and peripheral artery disease in East Asians and Europeans. Hum Genet 142, 965–980 (2023). https://doi.org/10.1007/s00439-023-02573-x

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