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Investigating the shared genetic architecture of uterine leiomyoma and breast cancer: A genome-wide cross-trait analysis

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机构： [1]Department of Epidemiology and Health Statistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan 610041, China [2]Department of Life Sciences, Sichuan University, Chengdu, Sichuan 610041, China [3]Department of Genetics, Harvard Medical School, Boston, MA 02115, USA [4]Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA [5]Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA [6]Department of Obstetrics and Gynecology, Brigham andWomen’s Hospital, Harvard Medical School, Boston, MA 02115, USA [7]Department of Pathology, Brigham andWomen’s Hospital, Harvard Medical School, Boston, MA 02115, USA [8]Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA [9]Manchester Centre for Audiology and Deafness, Manchester Academic Health Science Center, University of Manchester, Manchester M13 9PL, UK [10]Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Solna, Stockholm, Sweden [11]Program in Genetic Epidemiology and Statistical Genetics, Harvard T. H. Chan School of Public Health, Boston, MA, USA

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Little is known regarding the shared genetic architecture or causality underlying the phenotypic association observed for uterine leiomyoma (UL) and breast cancer (BC). Leveraging summary statistics from the hitherto largest genome-wide association study (GWAS) conducted in each trait, we investigated the genetic overlap and causal associations of UL with BC overall, as well as with its subtypes defined by the status of estrogen receptor (ER). We observed a positive genetic correlation between UL and BC overall (rg = 0.09, p = 6.00 × 10-3), which was consistent in ER+ subtype (rg = 0.06, p = 0.01) but not in ER- subtype (rg = 0.06, p = 0.08). Partitioning the whole genome into 1,703 independent regions, local genetic correlation was identified at 22q13.1 for UL with BC overall and with ER+ subtype. Significant genetic correlation was further discovered in 9 out of 14 functional categories, with the highest estimates observed in coding, H3K9ac, and repressed regions. Cross-trait meta-analysis identified 9 novel loci shared between UL and BC. Mendelian randomization demonstrated a significantly increased risk of BC overall (OR = 1.09, 95% CI = 1.01-1.18) and ER+ subtype (OR = 1.09, 95% CI = 1.01-1.17) for genetic liability to UL. No reverse causality was found. Our comprehensive genome-wide cross-trait analysis demonstrates a shared genetic basis, pleiotropic loci, as well as a putative causal relationship between UL and BC, highlighting an intrinsic link underlying these two complex female diseases.Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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出版当年[2022]版：

大类 | 1 区

生物学

小类 | 1 区遗传学

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大类 | 1 区

生物学

小类 | 1 区遗传学

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第一作者机构： [1]Department of Epidemiology and Health Statistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan 610041, China

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通讯机构： [1]Department of Epidemiology and Health Statistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan 610041, China [10]Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Solna, Stockholm, Sweden [11]Program in Genetic Epidemiology and Statistical Genetics, Harvard T. H. Chan School of Public Health, Boston, MA, USA

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