Genetic association of mosaic loss of chromosome Y with prostate cancer in men of European and East Asian ancestries: a Mendelian randomization study

Kobayashi, Takuya; Hachiya, Tsuyoshi; Ikehata, Yoshihiro; Horie, Shigeo

doi:10.3389/fragi.2023.1176451

Cited by 9 publications

(4 citation statements)

References 49 publications

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“…19; Supplementary Data 21). Our finding that mLOY status increases the risk of prostate cancer (OR=1.061 [1.031, 1.092]) is in agreement with a recent study using the PRACTICAL Consortium 39 .…”

Section: Univariable and Multivariable Mendelian Randomizationsupporting

confidence: 92%

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Multi-ancestry genome-wide association meta-analysis of mosaic loss of chromosome Y in the Million Veteran Program identifies 167 novel loci

Francis,

Gorman,

Bigdeli

et al. 2024

Preprint

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Mosaic loss of chromosome Y (mLOY) is a common somatic mutation in leukocytes of older males. mLOY was detected in 126,108 participants of the Million Veteran Program: 106,054 European (EUR), 13,927 admixed African (AFR), and 6,127 Hispanic. In multi-ancestry genome-wide association analysis, we identified 323 genome-wide significant loci, 167 of which were novel—more than doubling the number of known mLOY loci. Tract-based ancestry deconvolution resolved local inflation at AFR lead SNPs. Transcriptome-wide associations yielded 2,297 significant genes, including seven additional novel genes; integrative eQTL analyses highlighted 51 genes that causally influence mLOY via differential expression. Thirty-two significant traits found in a phenome-wide polygenic score scan were used in Mendelian randomization (MR). MR implicated six traits as causal influences on mLOY: triglycerides, high-density lipoprotein, smoking, body mass index, testosterone, and sex hormone-binding globulin; and found influence of mLOY on plateletcrit, prostate cancer, lymphocyte percentage, and neutrophil percentage. These results mark a major step forward in our understanding of the genetic architecture of mLOY and its associated risks.

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Section: Univariable and Multivariable Mendelian Randomizationsupporting

confidence: 92%

“…In addition to replicating the result that mLOY can increase risk of prostate cancer 39 ; reverse MR indicated a significant causal influence of mLOY on increased plateletcrit, increased neutrophil percentage, and decreased lymphocyte percentage.…”

Section: Discussionmentioning

confidence: 76%

Multi-ancestry genome-wide association meta-analysis of mosaic loss of chromosome Y in the Million Veteran Program identifies 167 novel loci

Francis,

Gorman,

Bigdeli

et al. 2024

Preprint

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“…These two parts are then used to determine the direction of a possible causal effect between the two phenotypes (21,22). Furthermore, MR-PRESSO was used to assess horizontal pleiotropy in the results that demonstrate causality (23,24). MR results were defined as statistically significant at two-sided P<0.05.…”

Section: Discussionmentioning

confidence: 99%

Association of genetically determined chronotype with circulating testosterone: a Mendelian randomization study

Ichikawa,

Kobayashi,

Hachiya

et al. 2024

Front. Endocrinol.

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Low testosterone levels in men have been linked to decreased physical and mental function, as well as a reduced quality of life. Previous prospective observational studies have suggested an association between testosterone and sleep traits, but the causality of this relationship remains unclear. We aimed to explore the potential causal link between genetically determined sleep traits and testosterone levels in men using Mendelian randomization (MR) analysis from the UK Biobank dataset. Our exposures were genetic variants associated with sleep traits (chronotype and sleep duration), whereas our outcomes were traits of sex steroid hormones (total testosterone, TT; bioavailable testosterone, BAT; and sex hormone-binding globulin, SHBG). We employed inverse variance weighted (IVW) and weighted median (WM) methods to assess the causal associations. The IVW method offers a robust estimate of causality, whereas the WM method provides reliable results even when some genetic variants are invalid instruments. Our main analysis involving sex steroid hormones and chronotype identified 155 chronotype-related variants. The primary findings from the analysis, which used chronotype as the exposure and sex steroid hormones as the outcomes, showed that a genetically predicted chronotype score was significantly associated with an increased levels of TT (association coefficient β, 0.08; 95% confidence interval [CI], 0.02–0.14; P = 0.008) and BAT (β, 0.08; 95% CI, 0.02–0.14; P = 0.007), whereas there was no significant association with SHBG (β, 0.01; 95% CI, −0.02–0.03; P = 0.64). Meanwhile, MR analysis of sex steroid hormones and sleep duration was performed, and 69 variants associated with sleep duration were extracted. There were no significant association between sleep duration and sex steroid hormones (TT, P = 0.91; BAT, P = 0.82; and SHBG, P = 0.95). Our data support a causal association between chronotype and circulating testosterone levels in men. These findings underscore a potential causal relationship between chronotype and testosterone levels in men, suggesting that lifestyle adjustments are crucial for men’s health. Recognizing factors that influence testosterone is essential. One limitation of this study is the use of one-sample MR, which can introduce potential bias due to non-independence of genetic associations for exposure and outcome. In conclusion, our findings indicate that a morning preference is correlated with circulating testosterone levels, emphasizing the potential impact of lifestyle habits on testosterone levels in men.

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“…GWAS variants significantly associated with mLOY are enriched among genes implicated in cell cycle regulation, hematologic malignancies and cancer susceptibility, suggesting the shared genetic architecture between mLOY and cancer susceptibility (14)(15)(16). mLOY increases the risk of prostate cancer (17), and mLOY is on the causal pathway of increased aspartate transaminase (AST) (18). Survival analysis reveals the association of mLOY in blood and the increased risk of all-cause mortality and non-haematological cancer mortality (19).…”

Section: )mentioning

confidence: 99%

Association between mosaic loss of chromosome Y and pulmonary fibrosis susceptibility and severity

Wang,

Hadad,

Moss

et al. 2024

Preprint

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BackgroundPulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and multiple interconnected underlying biological mechanisms. Mosaic loss of chromosome Y (mLOY) is one of the most common forms of acquired chromosome abnormality in men, which has been reported to be associated with increased risk of various chronic progressive diseases including fibrotic diseases. However, the exact role of mLOY in the development of PF remains elusive and to be elucidated.MethodsWe adopted three complementary approaches to explore the role of mLOY in the pathogenesis of PF. We used copy number on chromosome Y to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. We performed Mendelian randomisation to examine the causal relationship between mLOY, IPF, and telomere length.ResultsThe genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (P = 0.0032). mLOY is related to age (P = 0.00021) and shorter telomere length (P = 0.0081) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells and appears to be related to presence and severity of fibrosis. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY.ConclusionOur study confirms the existence of mLOY in PF patients and suggests that mLOY is not a major driver of IPF. The combined evidence suggests a triangulation model where telomere shortening leads to both IPF and mLOY.

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Genetic association of mosaic loss of chromosome Y with prostate cancer in men of European and East Asian ancestries: a Mendelian randomization study

Cited by 9 publications

References 49 publications

Multi-ancestry genome-wide association meta-analysis of mosaic loss of chromosome Y in the Million Veteran Program identifies 167 novel loci

Multi-ancestry genome-wide association meta-analysis of mosaic loss of chromosome Y in the Million Veteran Program identifies 167 novel loci

Association of genetically determined chronotype with circulating testosterone: a Mendelian randomization study

Association between mosaic loss of chromosome Y and pulmonary fibrosis susceptibility and severity

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