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    Genetic Aspects of Mammographic Density Measures Associated with Breast Cancer Risk
    Li, S ; Nguyen, TL ; Tu, N-D ; Dowty, JG ; Dite, GS ; Ye, Z ; Trinh, HN ; Evans, CF ; Tan, M ; Sung, J ; Jenkins, MA ; Giles, GG ; Hopper, JL ; Southey, MC (MDPI, 2022-06-01)
    Cumulus, Altocumulus, and Cirrocumulus are measures of mammographic density defined at increasing pixel brightness thresholds, which, when converted to mammogram risk scores (MRSs), predict breast cancer risk. Twin and family studies suggest substantial variance in the MRSs could be explained by genetic factors. For 2559 women aged 30 to 80 years (mean 54 years), we measured the MRSs from digitized film mammograms and estimated the associations of the MRSs with a 313-SNP breast cancer polygenic risk score (PRS) and 202 individual SNPs associated with breast cancer risk. The PRS was weakly positively correlated (correlation coefficients ranged 0.05-0.08; all p < 0.04) with all the MRSs except the Cumulus-white MRS based on the "white but not bright area" (correlation coefficient = 0.04; p = 0.06). After adjusting for its association with the Altocumulus MRS, the PRS was not associated with the Cumulus MRS. There were MRS associations (Bonferroni-adjusted p < 0.04) with one SNP in the ATXN1 gene and nominally with some ESR1 SNPs. Less than 1% of the variance of the MRSs is explained by the genetic markers currently known to be associated with breast cancer risk. Discovering the genetic determinants of the bright, not white, regions of the mammogram could reveal substantial new genetic causes of breast cancer.
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    Streamlined genetic education is effective in preparing women newly diagnosed with breast cancer for decision making about treatment-focused genetic testing: a randomized controlled noninferiority trial
    Quinn, VF ; Meiser, B ; Kirk, J ; Tucker, KM ; Watts, KJ ; Rahman, B ; Peate, M ; Saunders, C ; Geelhoed, E ; Gleeson, M ; Barlow-Stewart, K ; Field, M ; Harris, M ; Antill, YC ; Cicciarelli, L ; Crowe, K ; Bowen, MT ; Mitchell, G (NATURE PUBLISHING GROUP, 2017-04-01)
    PURPOSE: Increasingly, women newly diagnosed with breast cancer are being offered treatment-focused genetic testing (TFGT). As the demand for TFGT increases, streamlined methods of genetic education are needed. METHODS: In this noninferiority trial, women aged <50 years with either a strong family history (FH+) or other features suggestive of a germ-line mutation (FH-) were randomized before definitive breast cancer surgery to receive TFGT education either as brief written materials (intervention group (IG)) or during a genetic counseling session at a familial cancer clinic (usual-care group (UCG)). Women completed self-report questionnaires at four time points over 12 months. RESULTS: A total of 135 women were included in the analysis, all of whom opted for TFGT. Decisional conflict about TFGT choice (primary outcome) was not inferior in the IG compared with the UCG (noninferiority margin of -10; mean difference = 2.45; 95% confidence interval -2.87-7.76; P = 0.36). Costs per woman counseled in the IG were significantly lower (AUD$89) compared with the UCG (AUD$173; t(115) = 6.02; P < 0.001). CONCLUSION: A streamlined model of educating women newly diagnosed with breast cancer about TFGT seems to be a cost-effective way of delivering education while ensuring that women feel informed and supported in their decision making, thus freeing resources for other women to access TFGT.Genet Med 19 4, 448-456.
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    Residential surrounding greenness and DNA methylation: an epigenome-wide association study
    Xu, R ; Li, S ; Li, S ; Wong, EM ; Southey, MC ; Hopper, JL ; Abramson, MJ ; Guo, Y (Environmental Health Perspectives, 2021-08-23)
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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.
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    Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium
    Morra, A ; Jung, AY ; Behrens, S ; Keeman, R ; Ahearn, TU ; Anton-Culver, H ; Arndt, V ; Augustinsson, A ; Auvinen, PK ; Freeman, LEB ; Becher, H ; Beckmann, MW ; Blomqvist, C ; Bojesen, SE ; Bolla, MK ; Brenner, H ; Briceno, I ; Brucker, SY ; Camp, NJ ; Campa, D ; Canzian, F ; Castelao, JE ; Chanock, SJ ; Choi, J-Y ; Clarke, CL ; Couch, FJ ; Cox, A ; Cross, SS ; Czene, K ; Dork, T ; Dunning, AM ; Dwek, M ; Easton, DF ; Eccles, DM ; Egan, KM ; Evans, DG ; Fasching, PA ; Flyger, H ; Gago-Dominguez, M ; Gapstur, SM ; Garcia-Saenz, JA ; Gaudet, MM ; Giles, GG ; Grip, M ; Guenel, P ; Haiman, CA ; Hakansson, N ; Hall, P ; Hamann, U ; Han, SN ; Hart, SN ; Hartman, M ; Heyworth, JS ; Hoppe, R ; Hopper, JL ; Hunter, DJ ; Ito, H ; Jager, A ; Jakimovska, M ; Jakubowska, A ; Janni, W ; Kaaks, R ; Kang, D ; Kapoor, PM ; Kitahara, CM ; Koutros, S ; Kraft, P ; Kristensen, VN ; Lacey, J ; Lambrechts, D ; Le Marchand, L ; Li, J ; Lindblom, A ; Lush, M ; Mannermaa, A ; Manoochehri, M ; Margolin, S ; Mariapun, S ; Matsuo, K ; Mavroudis, D ; Milne, RL ; Muranen, TA ; Newman, WG ; Noh, D-Y ; Nordestgaard, BG ; Obi, N ; Olshan, AF ; Olsson, H ; Park-Simon, T-W ; Petridis, C ; Pharoah, PDP ; Plaseska-Karanfilska, D ; Presneau, N ; Rashid, MU ; Rennert, G ; Rennert, HS ; Rhenius, V ; Romero, A ; Saloustros, E ; Sawyer, EJ ; Schneeweiss, A ; Schwentner, L ; Scott, C ; Shah, M ; Shen, C-Y ; Shu, X-O ; Southey, MC ; Stram, DO ; Tamimi, RM ; Tapper, W ; Tollenaar, RAEM ; Tomlinson, I ; Torres, D ; Troester, MA ; Truong, T ; Vachon, CM ; Wang, Q ; Wang, SS ; Williams, JA ; Winqvist, R ; Wolk, A ; Wu, AH ; Yoo, K-Y ; Yu, J-C ; Zheng, W ; Ziogas, A ; Yang, XR ; Eliassen, AH ; Holmes, MD ; Garcia-Closas, M ; Teo, SH ; Schmidt, MK ; Chang-Claude, J (AMER ASSOC CANCER RESEARCH, 2021-04-01)
    BACKGROUND: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. METHODS: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. RESULTS: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (P adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking. CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
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    Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects
    Howe, LJ ; Nivard, MG ; Morris, TT ; Hansen, AF ; Rasheed, H ; Cho, Y ; Chittoor, G ; Ahlskog, R ; Lind, PA ; Palviainen, T ; van der Zee, MD ; Cheesman, R ; Mangino, M ; Wang, Y ; Li, S ; Klaric, L ; Ratliff, SM ; Bielak, LF ; Nygaard, M ; Giannelis, A ; Willoughby, EA ; Reynolds, CA ; Balbona, JV ; Andreassen, OA ; Ask, H ; Baras, A ; Bauer, CR ; Boomsma, DI ; Campbell, A ; Campbell, H ; Chen, Z ; Christofidou, P ; Corfield, E ; Dahm, CC ; Dokuru, DR ; Evans, LM ; de Geus, EJC ; Giddaluru, S ; Gordon, SD ; Harden, KP ; Hill, WD ; Hughes, A ; Kerr, SM ; Kim, Y ; Kweon, H ; Latvala, A ; Lawlor, DA ; Li, L ; Lin, K ; Magnus, P ; Magnusson, PKE ; Mallard, TT ; Martikainen, P ; Mills, MC ; Njolstad, PR ; Overton, JD ; Pedersen, NL ; Porteous, DJ ; Reid, J ; Silventoinen, K ; Southey, MC ; Stoltenberg, C ; Tucker-Drob, EM ; Wright, MJ ; Kweon, H ; Hewitt, JK ; Keller, MC ; Stallings, MC ; Lee, JJ ; Christensen, K ; Kardia, SLR ; Peyser, PA ; Smith, JA ; Wilson, JF ; Hopper, JL ; Hagg, S ; Spector, TD ; Pingault, J-B ; Plomin, R ; Havdahl, A ; Bartels, M ; Martin, NG ; Oskarsson, S ; Justice, AE ; Millwood, IY ; Hveem, K ; Naess, O ; Willer, CJ ; Asvold, BO ; Koellinger, PD ; Kaprio, J ; Medland, SE ; Walters, RG ; Benjamin, DJ ; Turley, P ; Evans, DM ; Smith, GD ; Hayward, C ; Brumpton, B ; Hemani, G ; Davies, NM (NATURE PORTFOLIO, 2022-05-09)
    Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.
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    Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing
    Southey, MC ; Dowty, JG ; Riaz, M ; Steen, JA ; Renault, A-L ; Tucker, K ; Kirk, J ; James, P ; Winship, I ; Pachter, N ; Poplawski, N ; Grist, S ; Park, DJ ; Pope, BJ ; Mahmood, K ; Hammet, F ; Mahmoodi, M ; Tsimiklis, H ; Theys, D ; Rewse, A ; Willis, A ; Morrow, A ; Speechly, C ; Harris, R ; Sebra, R ; Schadt, E ; Lacaze, P ; McNeil, JJ ; Giles, GG ; Milne, RL ; Hopper, JL ; Nguyen-Dumont, T (NATURE PORTFOLIO, 2021-12-09)
    Population-based estimates of breast cancer risk for carriers of pathogenic variants identified by gene-panel testing are urgently required. Most prior research has been based on women selected for high-risk features and more data is needed to make inference about breast cancer risk for women unselected for family history, an important consideration of population screening. We tested 1464 women diagnosed with breast cancer and 862 age-matched controls participating in the Australian Breast Cancer Family Study (ABCFS), and 6549 healthy, older Australian women enroled in the ASPirin in Reducing Events in the Elderly (ASPREE) study for rare germline variants using a 24-gene-panel. Odds ratios (ORs) were estimated using unconditional logistic regression adjusted for age and other potential confounders. We identified pathogenic variants in 11.1% of the ABCFS cases, 3.7% of the ABCFS controls and 2.2% of the ASPREE (control) participants. The estimated breast cancer OR [95% confidence interval] was 5.3 [2.1-16.2] for BRCA1, 4.0 [1.9-9.1] for BRCA2, 3.4 [1.4-8.4] for ATM and 4.3 [1.0-17.0] for PALB2. Our findings provide a population-based perspective to gene-panel testing for breast cancer predisposition and opportunities to improve predictors for identifying women who carry pathogenic variants in breast cancer predisposition genes.
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    Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk.
    Dareng, EO ; Tyrer, JP ; Barnes, DR ; Jones, MR ; Yang, X ; Aben, KKH ; Adank, MA ; Agata, S ; Andrulis, IL ; Anton-Culver, H ; Antonenkova, NN ; Aravantinos, G ; Arun, BK ; Augustinsson, A ; Balmaña, J ; Bandera, EV ; Barkardottir, RB ; Barrowdale, D ; Beckmann, MW ; Beeghly-Fadiel, A ; Benitez, J ; Bermisheva, M ; Bernardini, MQ ; Bjorge, L ; Black, A ; Bogdanova, NV ; Bonanni, B ; Borg, A ; Brenton, JD ; Budzilowska, A ; Butzow, R ; Buys, SS ; Cai, H ; Caligo, MA ; Campbell, I ; Cannioto, R ; Cassingham, H ; Chang-Claude, J ; Chanock, SJ ; Chen, K ; Chiew, Y-E ; Chung, WK ; Claes, KBM ; Colonna, S ; GEMO Study Collaborators, ; GC-HBOC Study Collaborators, ; EMBRACE Collaborators, ; Cook, LS ; Couch, FJ ; Daly, MB ; Dao, F ; Davies, E ; de la Hoya, M ; de Putter, R ; Dennis, J ; DePersia, A ; Devilee, P ; Diez, O ; Ding, YC ; Doherty, JA ; Domchek, SM ; Dörk, T ; du Bois, A ; Dürst, M ; Eccles, DM ; Eliassen, HA ; Engel, C ; Evans, GD ; Fasching, PA ; Flanagan, JM ; Fortner, RT ; Machackova, E ; Friedman, E ; Ganz, PA ; Garber, J ; Gensini, F ; Giles, GG ; Glendon, G ; Godwin, AK ; Goodman, MT ; Greene, MH ; Gronwald, J ; OPAL Study Group, ; AOCS Group, ; Hahnen, E ; Haiman, CA ; Håkansson, N ; Hamann, U ; Hansen, TVO ; Harris, HR ; Hartman, M ; Heitz, F ; Hildebrandt, MAT ; Høgdall, E ; Høgdall, CK ; Hopper, JL ; Huang, R-Y ; Huff, C ; Hulick, PJ ; Huntsman, DG ; Imyanitov, EN ; KConFab Investigators, ; HEBON Investigators, ; Isaacs, C ; Jakubowska, A ; James, PA ; Janavicius, R ; Jensen, A ; Johannsson, OT ; John, EM ; Jones, ME ; Kang, D ; Karlan, BY ; Karnezis, A ; Kelemen, LE ; Khusnutdinova, E ; Kiemeney, LA ; Kim, B-G ; Kjaer, SK ; Komenaka, I ; Kupryjanczyk, J ; Kurian, AW ; Kwong, A ; Lambrechts, D ; Larson, MC ; Lazaro, C ; Le, ND ; Leslie, G ; Lester, J ; Lesueur, F ; Levine, DA ; Li, L ; Li, J ; Loud, JT ; Lu, KH ; Lubiński, J ; Mai, PL ; Manoukian, S ; Marks, JR ; Matsuno, RK ; Matsuo, K ; May, T ; McGuffog, L ; McLaughlin, JR ; McNeish, IA ; Mebirouk, N ; Menon, U ; Miller, A ; Milne, RL ; Minlikeeva, A ; Modugno, F ; Montagna, M ; Moysich, KB ; Munro, E ; Nathanson, KL ; Neuhausen, SL ; Nevanlinna, H ; Yie, JNY ; Nielsen, HR ; Nielsen, FC ; Nikitina-Zake, L ; Odunsi, K ; Offit, K ; Olah, E ; Olbrecht, S ; Olopade, OI ; Olson, SH ; Olsson, H ; Osorio, A ; Papi, L ; Park, SK ; Parsons, MT ; Pathak, H ; Pedersen, IS ; Peixoto, A ; Pejovic, T ; Perez-Segura, P ; Permuth, JB ; Peshkin, B ; Peterlongo, P ; Piskorz, A ; Prokofyeva, D ; Radice, P ; Rantala, J ; Riggan, MJ ; Risch, HA ; Rodriguez-Antona, C ; Ross, E ; Rossing, MA ; Runnebaum, I ; Sandler, DP ; Santamariña, M ; Soucy, P ; Schmutzler, RK ; Setiawan, VW ; Shan, K ; Sieh, W ; Simard, J ; Singer, CF ; Sokolenko, AP ; Song, H ; Southey, MC ; Steed, H ; Stoppa-Lyonnet, D ; Sutphen, R ; Swerdlow, AJ ; Tan, YY ; Teixeira, MR ; Teo, SH ; Terry, KL ; Terry, MB ; OCAC Consortium, ; CIMBA Consortium, ; Thomassen, M ; Thompson, PJ ; Thomsen, LCV ; Thull, DL ; Tischkowitz, M ; Titus, L ; Toland, AE ; Torres, D ; Trabert, B ; Travis, R ; Tung, N ; Tworoger, SS ; Valen, E ; van Altena, AM ; van der Hout, AH ; Van Nieuwenhuysen, E ; van Rensburg, EJ ; Vega, A ; Edwards, DV ; Vierkant, RA ; Wang, F ; Wappenschmidt, B ; Webb, PM ; Weinberg, CR ; Weitzel, JN ; Wentzensen, N ; White, E ; Whittemore, AS ; Winham, SJ ; Wolk, A ; Woo, Y-L ; Wu, AH ; Yan, L ; Yannoukakos, D ; Zavaglia, KM ; Zheng, W ; Ziogas, A ; Zorn, KK ; Kleibl, Z ; Easton, D ; Lawrenson, K ; DeFazio, A ; Sellers, TA ; Ramus, SJ ; Pearce, CL ; Monteiro, AN ; Cunningham, J ; Goode, EL ; Schildkraut, JM ; Berchuck, A ; Chenevix-Trench, G ; Gayther, SA ; Antoniou, AC ; Pharoah, PDP (Springer Science and Business Media LLC, 2022-05)
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    Improved definition of growing pains: A common familial primary pain disorder of early childhood.
    Champion, GD ; Bui, M ; Sarraf, S ; Donnelly, TJ ; Bott, AN ; Goh, S ; Jaaniste, T ; Hopper, J (Wiley, 2022-06)
    Background: Commonly applied diagnostic criteria for growing pains (GP) have evolved without determination by an authoritative representative body. GP and restless legs syndrome (RLS) share anatomical, distributional, temporal, and other clinical features and are associated in individuals over time, in families, and in population samples. In this study, we tested the hypothesis that GP, diagnosed by widely used criteria, is confounded by cases of painful restless legs syndrome (RLS-Painful). Methods: A twin family study of genetic influence and associations of GP using questionnaires was administered by Twins Research Australia. Twins (3-18 years; monozygous 503, dizygous 513), their oldest siblings, mothers, and fathers were randomly selected from the twin registry. Family members completed the questionnaires assessing lifetime prevalence of GP by commonly applied criteria and covariates including the history of iron deficiency and pediatric pain disorders. A GP-Specific phenotype was defined as GP without urge to move the legs. We determined similarities in twin pairs for the GP and GP-Specific phenotypes, family associations, and estimated familial and individual-specific associations for each phenotype. Results: Lifetime prevalence was one-third lower for GP-Specific than for GP among the twin and family members. Monozygous twin pairs were more similar than dizygous twin pairs for GP and for the derived GP-Specific phenotype by three methods, consistent with genetic influence. There were familial associations, but the essential evidence for genetic influence was the twin-cotwin data. GP was associated, in multivariable analyses, with migraine, headaches, recurrent abdominal pain, and iron deficiency, while GP-Specific associations were limited to migraine and headaches. Conclusions: GP is hybrid, one-third of cases having symptoms and associations of RLS, necessarily RLS-Painful. GP-Specific (without symptoms and associations of RLS) could have a genetic etiology. We propose new criteria to facilitate etiological and therapeutic research.
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    Genome-wide and transcriptome-wide association studies of mammographic density phenotypes reveal novel loci
    Chen, H ; Fan, S ; Stone, J ; Thompson, DJ ; Douglas, J ; Li, S ; Scott, C ; Bolla, MK ; Wang, Q ; Dennis, J ; Michailidou, K ; Li, C ; Peters, U ; Hopper, JL ; Southey, MC ; Nguyen-Dumont, T ; Nguyen, TL ; Fasching, PA ; Behrens, A ; Cadby, G ; Murphy, RA ; Aronson, K ; Howell, A ; Astley, S ; Couch, F ; Olson, J ; Milne, RL ; Giles, GG ; Haiman, CA ; Maskarinec, G ; Winham, S ; John, EM ; Kurian, A ; Eliassen, H ; Andrulis, I ; Evans, DG ; Newman, WG ; Hall, P ; Czene, K ; Swerdlow, A ; Jones, M ; Pollan, M ; Fernandez-Navarro, P ; McConnell, DS ; Kristensen, VN ; Rothstein, JH ; Wang, P ; Habel, LA ; Sieh, W ; Dunning, AM ; Pharoah, PDP ; Easton, DF ; Gierach, GL ; Tamimi, RM ; Vachon, CM ; Lindstrom, S (BMC, 2022-04-12)
    BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.