Melbourne School of Population and Global Health - Research Publications

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    Incorporating progesterone receptor expression into the PREDICT breast prognostic model
    Grootes, I ; Keeman, R ; Blows, FM ; Milne, RL ; Giles, GG ; Swerdlow, AJ ; Fasching, PA ; Abubakar, M ; Andrulis, IL ; Anton-Culver, H ; Beckmann, MW ; Blomqvist, C ; Bojesen, SE ; Bolla, MK ; Bonanni, B ; Briceno, I ; Burwinkel, B ; Camp, NJ ; Castelao, JE ; Choi, J-Y ; Clarke, CL ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Devilee, P ; Dork, T ; Dunning, AM ; Dwek, M ; Easton, DF ; Eccles, DM ; Eriksson, M ; Ernst, K ; Evans, DG ; Figueroa, JD ; Fink, V ; Floris, G ; Fox, S ; Gabrielson, M ; Gago-Dominguez, M ; Garcia-Saenz, JA ; Gonzalez-Neira, A ; Haeberle, L ; Haiman, CA ; Hall, P ; Hamann, U ; Harkness, EF ; Hartman, M ; Hein, A ; Hooning, MJ ; Hou, M-F ; Howell, SJ ; Ito, H ; Jakubowska, A ; Janni, W ; John, EM ; Jung, A ; Kang, D ; Kristensen, VN ; Kwong, A ; Lambrechts, D ; Li, J ; Manoochehri, M ; Margolin, S ; Matsuo, K ; Taib, NAM ; Mulligan, AM ; Nevanlinna, H ; Newman, WG ; Offit, K ; Osorio, A ; Park, SK ; Park-Simon, T-W ; Patel, A ; Presneau, N ; Pylkas, K ; Rack, B ; Radice, P ; Rennert, G ; Romero, A ; Saloustros, E ; Sawyer, EJ ; Schneeweiss, A ; Schochter, F ; Schoemaker, MJ ; Shen, C-Y ; Shibli, R ; Sinn, P ; Tapper, WJ ; Tawfiq, E ; Teo, SH ; Teras, LR ; Torres, D ; Vachon, CM ; van Deurzen, CHM ; Wendt, C ; Williams, JA ; Winqvist, R ; Elwood, M ; Schmidt, MK ; Pharoah, PDP (ELSEVIER SCI LTD, 2022-09-01)
    BACKGROUND: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2). METHOD: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance. RESULTS: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted. CONCLUSION: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.
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    Absolute Risk of Oropharyngeal Cancer After an HPV16-E6 Serology Test and Potential Implications for Screening: Results From the Human Papillomavirus Cancer Cohort Consortium.
    Robbins, HA ; Ferreiro-Iglesias, A ; Waterboer, T ; Brenner, N ; Nygard, M ; Bender, N ; Schroeder, L ; Hildesheim, A ; Pawlita, M ; D'Souza, G ; Visvanathan, K ; Langseth, H ; Schlecht, NF ; Tinker, LF ; Agalliu, I ; Wassertheil-Smoller, S ; Ness-Jensen, E ; Hveem, K ; Grioni, S ; Kaaks, R ; Sánchez, M-J ; Weiderpass, E ; Giles, GG ; Milne, RL ; Cai, Q ; Blot, WJ ; Zheng, W ; Weinstein, SJ ; Albanes, D ; Huang, W-Y ; Freedman, ND ; Kreimer, AR ; Johansson, M ; Brennan, P (American Society of Clinical Oncology (ASCO), 2022-11-01)
    PURPOSE: Seropositivity for the HPV16-E6 oncoprotein is a promising marker for early detection of oropharyngeal cancer (OPC), but the absolute risk of OPC after a positive or negative test is unknown. METHODS: We constructed an OPC risk prediction model that integrates (1) relative odds of OPC for HPV16-E6 serostatus and cigarette smoking from the human papillomavirus (HPV) Cancer Cohort Consortium (HPVC3), (2) US population risk factor data from the National Health Interview Survey, and (3) US sex-specific population rates of OPC and mortality. RESULTS: The nine HPVC3 cohorts included 365 participants with OPC with up to 10 years between blood draw and diagnosis and 5,794 controls. The estimated 10-year OPC risk for HPV16-E6 seropositive males at age 50 years was 17.4% (95% CI, 12.4 to 28.6) and at age 60 years was 27.1% (95% CI, 19.2 to 45.4). Corresponding 5-year risk estimates were 7.3% and 14.4%, respectively. For HPV16-E6 seropositive females, 10-year risk estimates were 3.6% (95% CI, 2.5 to 5.9) at age 50 years and 5.5% (95% CI, 3.8 to 9.2) at age 60 years and 5-year risk estimates were 1.5% and 2.7%, respectively. Over 30 years, after a seropositive result at age 50 years, an estimated 49.9% of males and 13.3% of females would develop OPC. By contrast, 10-year risks among HPV16-E6 seronegative people were very low, ranging from 0.01% to 0.25% depending on age, sex, and smoking status. CONCLUSION: We estimate that a substantial proportion of HPV16-E6 seropositive individuals will develop OPC, with 10-year risks of 17%-27% for males and 4%-6% for females age 50-60 years in the United States. This high level of risk may warrant periodic, minimally invasive surveillance after a positive HPV16-E6 serology test, particularly for males in high-incidence regions. However, an appropriate clinical protocol for surveillance remains to be established.
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    Weight is More Informative than Body Mass Index for Predicting Postmenopausal Breast Cancer Risk: Prospective Family Study Cohort (ProF-SC)
    Ye, Z ; Li, S ; Dite, GS ; Nguyen, TL ; MacInnis, RJ ; Andrulis, IL ; Buys, SS ; Daly, MB ; John, EM ; Kurian, AW ; Genkinger, JM ; Chung, WK ; Phillips, K-A ; Thorne, H ; Winship, IM ; Milne, RL ; Dugue, P-A ; Southey, MC ; Giles, GG ; Terry, MB ; Hopper, JL (AMER ASSOC CANCER RESEARCH, 2022-03-01)
    UNLABELLED: We considered whether weight is more informative than body mass index (BMI) = weight/height2 when predicting breast cancer risk for postmenopausal women, and if the weight association differs by underlying familial risk. We studied 6,761 women postmenopausal at baseline with a wide range of familial risk from 2,364 families in the Prospective Family Study Cohort. Participants were followed for on average 11.45 years and there were 416 incident breast cancers. We used Cox regression to estimate risk associations with log-transformed weight and BMI after adjusting for underlying familial risk. We compared model fits using the Akaike information criterion (AIC) and nested models using the likelihood ratio test. The AIC for the weight-only model was 6.22 units lower than for the BMI-only model, and the log risk gradient was 23% greater. Adding BMI or height to weight did not improve fit (ΔAIC = 0.90 and 0.83, respectively; both P = 0.3). Conversely, adding weight to BMI or height gave better fits (ΔAIC = 5.32 and 11.64; P = 0.007 and 0.0002, respectively). Adding height improved only the BMI model (ΔAIC = 5.47; P = 0.006). There was no evidence that the BMI or weight associations differed by underlying familial risk (P > 0.2). Weight is more informative than BMI for predicting breast cancer risk, consistent with nonadipose as well as adipose tissue being etiologically relevant. The independent but multiplicative associations of weight and familial risk suggest that, in terms of absolute breast cancer risk, the association with weight is more important the greater a woman's underlying familial risk. PREVENTION RELEVANCE: Our results suggest that the relationship between BMI and breast cancer could be due to a relationship between weight and breast cancer, downgraded by inappropriately adjusting for height; potential importance of anthropometric measures other than total body fat; breast cancer risk associations with BMI and weight are across a continuum.
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    Inflammation and Epigenetic Aging Are Largely Independent Markers of Biological Aging and Mortality
    Cribb, L ; Hodge, AM ; Yu, C ; Li, SX ; English, DR ; Makalic, E ; Southey, MC ; Milne, RL ; Giles, GG ; Dugue, P-A ; Le Couteur, D (OXFORD UNIV PRESS INC, 2022-08-04)
    Limited evidence exists on the link between inflammation and epigenetic ageing. We aimed to 1) assess the cross-sectional and prospective associations of 22 inflammation-related plasma markers and a signature of inflammaging with epigenetic ageing; 2) determine whether epigenetic ageing and inflammaging are independently associated with mortality. Blood samples from 940 participants in the Melbourne Collaborative Cohort Study, collected at baseline (1990-1994) and follow-up (2003-2007) were assayed for DNA methylation and 22 inflammation-related markers, including well-established markers (e.g., interleukins and C-reactive protein) and metabolites of the tryptophan-kynurenine pathway. Four measures of epigenetic ageing (PhenoAge, GrimAge, DunedinPoAm and Zhang) and a signature of inflammaging were considered, adjusted for age, and transformed to Z-scores. Associations were assessed using linear regression, and mortality hazard ratios (HR) and 95% confidence intervals (95%CI) were estimated using Cox regression. Cross-sectionally, most inflammation-related markers were associated with epigenetic ageing measures, although with generally modest effect sizes (regression coefficients per SD≤0.26) and explaining altogether between 1% and 11% of their variation. Prospectively, baseline inflammation-related markers were not, or only weakly, associated with epigenetic ageing after 11 years of follow-up. Epigenetic ageing and inflammaging were strongly and independently associated with mortality, e.g. inflammaging: HR=1.41, 95%CI=1.27-1.56, P=2x10-10; which was only slightly attenuated after adjustment for four epigenetic ageing measures: HR=1.35, 95%CI=1.22-1.51, P=7x10-9). Although cross-sectionally associated with epigenetic ageing, inflammation-related markers accounted for a modest proportion of its variation. Inflammaging and epigenetic ageing are essentially non-overlapping markers of biological ageing and may be used jointly to predict mortality.
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    Segregation analysis of 17,425 population-based breast cancer families: Evidence for genetic susceptibility and risk prediction
    Li, S ; MacInnis, RJ ; Lee, A ; Nguyen-Dumont, T ; Dorling, L ; Carvalho, S ; Dite, GS ; Shah, M ; Luccarini, C ; Wang, Q ; Milne, RL ; Jenkins, MA ; Giles, GG ; Dunning, AM ; Pharoah, PDP ; Southey, MC ; Easton, DF ; Hopper, JL ; Antoniou, AC (CELL PRESS, 2022-10-06)
    Rare pathogenic variants in known breast cancer-susceptibility genes and known common susceptibility variants do not fully explain the familial aggregation of breast cancer. To investigate plausible genetic models for the residual familial aggregation, we studied 17,425 families ascertained through population-based probands, 86% of whom were screened for pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM, and TP53 via gene-panel sequencing. We conducted complex segregation analyses and fitted genetic models in which breast cancer incidence depended on the effects of known susceptibility genes and other unidentified major genes and a normally distributed polygenic component. The proportion of familial variance explained by the six genes was 46% at age 20-29 years and decreased steadily with age thereafter. After allowing for these genes, the best fitting model for the residual familial variance included a recessive risk component with a combined genotype frequency of 1.7% (95% CI: 0.3%-5.4%) and a penetrance to age 80 years of 69% (95% CI: 38%-95%) for homozygotes, which may reflect the combined effects of multiple variants acting in a recessive manner, and a polygenic variance of 1.27 (95% CI: 0.94%-1.65), which did not vary with age. The proportion of the residual familial variance explained by the recessive risk component was 40% at age 20-29 years and decreased with age thereafter. The model predicted age-specific familial relative risks consistent with those observed by large epidemiological studies. The findings have implications for strategies to identify new breast cancer-susceptibility genes and improve disease-risk prediction, especially at a young age.
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    Methylation-based markers of aging and lifestyle-related factors and risk of breast cancer: a pooled analysis of four prospective studies
    Dugue, P-A ; Bodelon, C ; Chung, FF ; Brewer, HR ; Ambatipudi, S ; Sampson, JN ; Cuenin, C ; Chajes, V ; Romieu, I ; Fiorito, G ; Sacerdote, C ; Krogh, V ; Panico, S ; Tumino, R ; Vineis, P ; Polidoro, S ; Baglietto, L ; English, D ; Severi, G ; Giles, GG ; Milne, RL ; Herceg, Z ; Garcia-Closas, M ; Flanagan, JM ; Southey, MC (BMC, 2022-09-06)
    BACKGROUND: DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer. METHODS: Using data from four prospective case-control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage. RESULTS: None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath 'age acceleration' (AA): OR per SD = 1.02, 95%CI: 0.95-1.10; AA-Hannum: OR = 1.03, 95%CI:0.95-1.12; PhenoAge: OR = 1.01, 95%CI: 0.94-1.09 and GrimAge: OR = 1.03, 95%CI: 0.94-1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01-1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics. CONCLUSION: We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.
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    Breast cancer risks associated with missense variants in breast cancer susceptibility genes.
    Dorling, L ; Carvalho, S ; Allen, J ; Parsons, MT ; Fortuno, C ; González-Neira, A ; Heijl, SM ; Adank, MA ; Ahearn, TU ; Andrulis, IL ; Auvinen, P ; Becher, H ; Beckmann, MW ; Behrens, S ; Bermisheva, M ; Bogdanova, NV ; Bojesen, SE ; Bolla, MK ; Bremer, M ; Briceno, I ; Camp, NJ ; Campbell, A ; Castelao, JE ; Chang-Claude, J ; Chanock, SJ ; Chenevix-Trench, G ; NBCS Collaborators, ; Collée, JM ; Czene, K ; Dennis, J ; Dörk, T ; Eriksson, M ; Evans, DG ; Fasching, PA ; Figueroa, J ; Flyger, H ; Gabrielson, M ; Gago-Dominguez, M ; García-Closas, M ; Giles, GG ; Glendon, G ; Guénel, P ; Gündert, M ; Hadjisavvas, A ; Hahnen, E ; Hall, P ; Hamann, U ; Harkness, EF ; Hartman, M ; Hogervorst, FBL ; Hollestelle, A ; Hoppe, R ; Howell, A ; kConFab Investigators, ; SGBCC Investigators, ; Jakubowska, A ; Jung, A ; Khusnutdinova, E ; Kim, S-W ; Ko, Y-D ; Kristensen, VN ; Lakeman, IMM ; Li, J ; Lindblom, A ; Loizidou, MA ; Lophatananon, A ; Lubiński, J ; Luccarini, C ; Madsen, MJ ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; Mavroudis, D ; Milne, RL ; Mohd Taib, NA ; Muir, K ; Nevanlinna, H ; Newman, WG ; Oosterwijk, JC ; Park, SK ; Peterlongo, P ; Radice, P ; Saloustros, E ; Sawyer, EJ ; Schmutzler, RK ; Shah, M ; Sim, X ; Southey, MC ; Surowy, H ; Suvanto, M ; Tomlinson, I ; Torres, D ; Truong, T ; van Asperen, CJ ; Waltes, R ; Wang, Q ; Yang, XR ; Pharoah, PDP ; Schmidt, MK ; Benitez, J ; Vroling, B ; Dunning, AM ; Teo, SH ; Kvist, A ; de la Hoya, M ; Devilee, P ; Spurdle, AB ; Vreeswijk, MPG ; Easton, DF (Springer Science and Business Media LLC, 2022-05-18)
    BACKGROUND: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
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    Mechanisms for the Sex-Specific Effect of H. Pylori on Risk of Gastroesophageal Reflux Disease and Barrett's Esophagus
    Wang, SE ; Dashti, SG ; Hodge, AM ; Dixon-Suen, SC ; Castano-Rodriguez, N ; Thomas, RJS ; Giles, GG ; Milne, RL ; Boussioutas, A ; Kendall, BJ ; English, DR (AMER ASSOC CANCER RESEARCH, 2022-08-01)
    BACKGROUND: Mechanisms for how Helicobacter pylori infection affects risk of gastroesophageal reflux disease (GERD) and Barrett's esophagus are incompletely understood and might differ by sex. METHODS: In a case-control study nested in the Melbourne Collaborative Cohort Study with 425 GERD cases and 169 Barrett's esophagus cases (identified at 2007-2010 follow-up), we estimated sex-specific odds ratios for participants who were H. pylori seronegative versus seropositive at baseline (1990-1994). To explore possible mechanisms, we (i) compared patterns of H. pylori-induced gastritis by sex using serum pepsinogen-I and gastrin-17 data and (ii) quantified the effect of H. pylori seronegativity on Barrett's esophagus mediated by GERD using causal mediation analysis. RESULTS: For men, H. pylori seronegativity was associated with 1.69-fold [95% confidence interval (CI), 1.03-2.75] and 2.28-fold (95% CI, 1.27-4.12) higher odds of GERD and Barrett's esophagus, respectively. No association was observed for women. H. pylori-induced atrophic antral gastritis was more common in men (68%) than in women (56%; P = 0.015). For men, 5 of the 15 per 1,000 excess Barrett's esophagus risk from being seronegative were mediated by GERD. CONCLUSIONS: Men, but not women, who were H. pylori seronegative had increased risks of GERD and Barrett's esophagus. A possible explanation might be sex differences in patterns of H. pylori-induced atrophic antral gastritis, which could lead to less erosive reflux for men. Evidence of GERD mediating the effect of H. pylori on Barrett's esophagus risk among men supports this proposed mechanism. IMPACT: The findings highlight the importance of investigating sex differences in the effect of H. pylori on risk of GERD and Barrett's esophagus in future studies.
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    Diet and risk of gastro-oesophageal reflux disease in the Melbourne Collaborative Cohort Study
    Wang, SE ; Hodge, AM ; Dashti, SG ; Dixon-Suen, SC ; Mitchell, H ; Thomas, RJS ; Williamson, EM ; Makalic, E ; Boussioutas, A ; Haydon, AM ; Giles, GG ; Milne, RL ; Kendall, BJ ; English, DR (CAMBRIDGE UNIV PRESS, 2021-10-01)
    OBJECTIVE: To examine associations between diet and risk of developing gastro-oesophageal reflux disease (GERD). DESIGN: Prospective cohort with a median follow-up of 15·8 years. Baseline diet was measured using a FFQ. GERD was defined as self-reported current or history of daily heartburn or acid regurgitation beginning at least 2 years after baseline. Sex-specific logistic regressions were performed to estimate OR for GERD associated with diet quality scores and intakes of nutrients, food groups and individual foods and beverages. The effect of substituting saturated fat for monounsaturated or polyunsaturated fat on GERD risk was examined. SETTING: Melbourne, Australia. PARTICIPANTS: A cohort of 20 926 participants (62 % women) aged 40-59 years at recruitment between 1990 and 1994. RESULTS: For men, total fat intake was associated with increased risk of GERD (OR 1·05 per 5 g/d; 95 % CI 1·01, 1·09; P = 0·016), whereas total carbohydrate (OR 0·89 per 30 g/d; 95 % CI 0·82, 0·98; P = 0·010) and starch intakes (OR 0·84 per 30 g/d; 95 % CI 0·75, 0·94; P = 0·005) were associated with reduced risk. Nutrients were not associated with risk for women. For both sexes, substituting saturated fat for polyunsaturated or monounsaturated fat did not change risk. For both sexes, fish, chicken, cruciferous vegetables and carbonated beverages were associated with increased risk, whereas total fruit and citrus were associated with reduced risk. No association was observed with diet quality scores. CONCLUSIONS: Diet is a possible risk factor for GERD, but food considered as triggers of GERD symptoms might not necessarily contribute to disease development. Potential differential associations for men and women warrant further investigation.
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    Genetic insights into biological mechanisms governing human ovarian ageing
    Ruth, KS ; Day, FR ; Hussain, J ; Martinez-Marchal, A ; Aiken, CE ; Azad, A ; Thompson, DJ ; Knoblochova, L ; Abe, H ; Tarry-Adkins, JL ; Gonzalez, JM ; Fontanillas, P ; Claringbould, A ; Bakker, OB ; Sulem, P ; Walters, RG ; Terao, C ; Turon, S ; Horikoshi, M ; Lin, K ; Onland-Moret, NC ; Sankar, A ; Hertz, EPT ; Timshel, PN ; Shukla, V ; Borup, R ; Olsen, KW ; Aguilera, P ; Ferrer-Roda, M ; Huang, Y ; Stankovic, S ; Timmers, PRHJ ; Ahearn, TU ; Alizadeh, BZ ; Naderi, E ; Andrulis, IL ; Arnold, AM ; Aronson, KJ ; Augustinsson, A ; Bandinelli, S ; Barbieri, CM ; Beaumont, RN ; Becher, H ; Beckmann, MW ; Benonisdottir, S ; Bergmann, S ; Bochud, M ; Boerwinkle, E ; Bojesen, SE ; Bolla, MK ; Boomsma, DI ; Bowker, N ; Brody, JA ; Broer, L ; Buring, JE ; Campbell, A ; Campbell, H ; Castelao, JE ; Catamo, E ; Chanock, SJ ; Chenevix-Trench, G ; Ciullo, M ; Corre, T ; Couch, FJ ; Cox, A ; Crisponi, L ; Cross, SS ; Cucca, F ; Czene, K ; Smith, GD ; de Geus, EJCN ; de Mutsert, R ; De Vivo, I ; Demerath, EW ; Dennis, J ; Dunning, AM ; Dwek, M ; Eriksson, M ; Esko, T ; Fasching, PA ; Faul, JD ; Ferrucci, L ; Franceschini, N ; Frayling, TM ; Gago-Dominguez, M ; Mezzavilla, M ; Garcia-Closas, M ; Gieger, C ; Giles, GG ; Grallert, H ; Gudbjartsson, DF ; Gudnason, V ; Guenel, P ; Haiman, CA ; Hakansson, N ; Hall, P ; Hayward, C ; He, C ; He, W ; Heiss, G ; Hoffding, MK ; Hopper, JL ; Hottenga, JJ ; Hu, F ; Hunter, D ; Ikram, MA ; Jackson, RD ; Joaquim, MDR ; John, EM ; Joshi, PK ; Karasik, D ; Kardia, SLR ; Kartsonaki, C ; Karlsson, R ; Kitahara, CM ; Kolcic, I ; Kooperberg, C ; Kraft, P ; Kurian, AW ; Kutalik, Z ; La Bianca, M ; LaChance, G ; Langenberg, C ; Launer, LJ ; Laven, JSE ; Lawlor, DA ; Le Marchand, L ; Li, J ; Lindblom, A ; Lindstrom, S ; Lindstrom, T ; Linet, M ; Liu, Y ; Liu, S ; Luan, J ; Magi, R ; Magnusson, PKE ; Mangino, M ; Mannermaa, A ; Marco, B ; Marten, J ; Martin, NG ; Mbarek, H ; McKnight, B ; Medland, SE ; Meisinger, C ; Meitinger, T ; Menni, C ; Metspalu, A ; Milani, L ; Milne, RL ; Montgomery, GW ; Mook-Kanamori, DO ; Mulas, A ; Mulligan, AM ; Murray, A ; Nalls, MA ; Newman, A ; Noordam, R ; Nutile, T ; Nyholt, DR ; Olshan, AF ; Olsson, H ; Painter, JN ; Patel, AV ; Pedersen, NL ; Perjakova, N ; Peters, A ; Peters, U ; Pharoah, PDP ; Polasek, O ; Porcu, E ; Psaty, BM ; Rahman, I ; Rennert, G ; Rennert, HS ; Ridker, PM ; Ring, SM ; Robino, A ; Rose, LM ; Rosendaal, FR ; Rossouw, J ; Rudan, I ; Rueedi, R ; Ruggiero, D ; Sala, CF ; Saloustros, E ; Sandler, DP ; Sanna, S ; Sawyer, EJ ; Sarnowski, C ; Schlessinger, D ; Schmidt, MK ; Schoemaker, MJ ; Schraut, KE ; Scott, C ; Shekari, S ; Shrikhande, A ; Smith, AV ; Smith, BH ; Smith, JA ; Sorice, R ; Southey, MC ; Spector, TD ; Spinelli, JJ ; Stampfer, M ; Stoeckl, D ; van Meurs, JBJ ; Strauch, K ; Styrkarsdottir, U ; Swerdlow, AJ ; Tanaka, T ; Teras, LR ; Teumer, A ; thorsteinsdottir, U ; Timpson, NJ ; Toniolo, D ; Traglia, M ; Troester, MA ; Truong, T ; Tyrrell, J ; Uitterlinden, AG ; Ulivi, S ; Vachon, CM ; Vitart, V ; Voelker, U ; Vollenweider, P ; Voelzke, H ; Wang, Q ; Wareham, NJ ; Weinberg, CR ; Weir, DR ; Wilcox, AN ; van Dijk, KW ; Willemsen, G ; Wilson, JF ; Wolffenbuttel, BHR ; Wolk, A ; Wood, AR ; Zhao, W ; Zygmunt, M ; Chen, Z ; Li, L ; Franke, L ; Burgess, S ; Deelen, P ; Pers, TH ; Grondahl, ML ; Andersen, CY ; Pujol, A ; Lopez-Contreras, AJ ; Daniel, JA ; Stefansson, K ; Chang-Claude, J ; van der Schouw, YT ; Lunetta, KL ; Chasman, DI ; Easton, DF ; Visser, JA ; Ozanne, SE ; Namekawa, SH ; Solc, P ; Murabito, JM ; Ong, KK ; Hoffmann, ER ; Murray, A ; Roig, I ; Perry, JRB (NATURE PORTFOLIO, 2021-08-04)
    Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.