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1. Dysregulation of the homeobox transcription factor gene HOXB13: role in prostate cancer

Author: Decker B and Ostrander EA
Subjects: Therapeutics. Pharmacology, RM1-950
Abstract: Brennan Decker1,2, Elaine A Ostrander1 1Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; 2Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, School of Clinical Medicine, University of Cambridge, Cambridge, UK Abstract: Prostate cancer (PC) is the most common noncutaneous cancer in men, and epidemiological studies suggest that about 40% of PC risk is heritable. Linkage analyses in hereditary PC families have identified multiple putative loci. However, until recently, identification of specific risk alleles has proven elusive. Cooney et al used linkage mapping and segregation analysis to identify a putative risk locus on chromosome 17q21-22. In search of causative variant(s) in genes from the candidate region, a novel, potentially deleterious G84E substitution in homeobox transcription factor gene HOXB13 was observed in multiple hereditary PC families. In follow-up testing, the G84E allele was enriched in cases, especially those with an early diagnosis or positive family history of disease. This finding was replicated by others, confirming HOXB13 as a PC risk gene. The HOXB13 protein plays diverse biological roles in embryonic development and terminally differentiated tissue. In tumor cell lines, HOXB13 participates in a number of biological functions, including coactivation and localization of the androgen receptor and FOXA1. However, no consensus role has emerged and many questions remain. All HOXB13 variants with a proposed role in PC risk are predicted to damage the protein and lie in domains that are highly conserved across species. The G84E variant has the strongest epidemiological support and lies in a highly conserved MEIS protein-binding domain, which binds cofactors required for activation. On the basis of epidemiological and biological data, the G84E variant likely modulates the interaction between the HOXB13 protein and the androgen receptor, as well as affecting FOXA1-mediated transcriptional programming. However, further studies of the mutated protein are required to clarify the mechanisms by which this translates into PC risk. Keywords: prostate cancer risk, HOXB13
Published: 2014

2. Associations of prostate cancer risk variants with disease aggressiveness: results of the NCI-SPORE Genetics Working Group analysis of 18,343 cases

Author: Helfand, BT, Roehl, KA, Cooper, PR, McGuire, BB, Fitzgerald, LM, Cancel-Tassin, G, Cornu, JN, Bauer, S, Van Blarigan, EL, Chen, X, Duggan, D, Ostrander, EA, Gwo-Shu, M, Zhang, ZF, Chang, SC, Jeong, S, Fontham, ETH, Smith, G, Mohler, JL, Berndt, SI, McDonnell, SK, Kittles, R, Rybicki, BA, Freedman, M, Kantoff, PW, Pomerantz, M, Breyer, JP, Smith, JR, Rebbeck, TR, Mercola, D, Isaacs, WB, Wiklund, F, Cussenot, O, Thibodeau, SN, Schaid, DJ, Cannon-Albright, L, Cooney, KA, Chanock, SJ, Stanford, JL, Chan, JM, Witte, J, Xu, J, Bensen, JT, Taylor, JA, and Catalona, WJ
Subjects: Genetics, Complementary and Alternative Medicine, Paediatrics and Reproductive Medicine, Genetics & Heredity
Abstract: Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer (PC). It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score (Gleason ≤6, 7, ≥8) and aggressiveness (non-aggressive, intermediate, and aggressive disease). Statistical analyses were used to compare the frequency of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 (G) was significantly and inversely associated with aggressive (OR = 0.77; 95 % CI 0.69–0.87) and high-grade disease (OR = 0.77; 95 % CI 0.68–0.86) in European men. Similar associations with aggressive (OR = 0.72; 95 % CI 0.58–0.89) and high-grade disease (OR = 0.69; 95 % CI 0.54–0.87) were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels (
Published: 2015

3. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

Author: Wang, A, Shen, J, Rodriguez, AA, Saunders, EJ, Chen, F, Janivara, R, Darst, BF, Sheng, X, Xu, Y, Chou, AJ, Benlloch, S, Dadaev, T, Brook, MN, Plym, A, Sahimi, A, Hoffman, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Laisk, T, Figuerêdo, J, Muir, K, Ito, S, Liu, X, Biobank Japan Project, Uchio, Y, Kubo, M, Kamatani, Y, Lophatananon, A, Wan, P, Andrews, C, Lori, A, Choudhury, PP, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Rentsch, CT, Cho, K, Mcmahon, BH, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, A, Stroomberg, HV, Batra, J, Chambers, S, Horvath, L, Clements, JA, Tilly, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, S, Cook, MB, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Koutros, S, Beane Freeman, LE, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Butler, EN, Mohler, JL, Taylor, JA, Kogevinas, M, Dierssen-Sotos, T, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Pilie, P, Yu, Y, Bohlender, RJ, Gu, J, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Brenner, H, Chen, X, Holleczek, B, Schöttker, B, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, CM, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Abraham, A, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, J, Petrovics, G, Casey, G, Wang, Y, Tettey, Y, Lachance, J, Tang, W, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Yamoah, K, Govindasami, K, Chokkalingam, AP, Keaton, JM, Hellwege, JN, Clark, PE, Jalloh, M, Gueye, SM, Niang, L, Ogunbiyi, O, Shittu, O, Amodu, O, Adebiyi, AO, Aisuodionoe-Shadrach, OI, Ajibola, HO, Jamda, MA, Oluwole, OP, Nwegbu, M, Adusei, B, Mante, S, Darkwa-Abrahams, A, Diop, H, Gundell, SM, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Kachuri, L, Varma, R, McKean-Cowdin, R, Torres, M, Preuss, MH, Loos, RJF, Zawistowski, M, Zöllner, S, Lu, Z, Van Den Eeden, SK, Easton, DF, Ambs, S, Edwards, TL, Mägi, R, Rebbeck, TR, Fritsche, L, Chanock, SJ, Berndt, SI, Wiklund, F, Nakagawa, H, Witte, JS, Gaziano, JM, Justice, AC, Mancuso, N, Terao, C, Eeles, RA, Kote-Jarai, Z, Madduri, RK, Conti, DV, Haiman, CA, Wang, A, Shen, J, Rodriguez, AA, Saunders, EJ, Chen, F, Janivara, R, Darst, BF, Sheng, X, Xu, Y, Chou, AJ, Benlloch, S, Dadaev, T, Brook, MN, Plym, A, Sahimi, A, Hoffman, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Laisk, T, Figuerêdo, J, Muir, K, Ito, S, Liu, X, Biobank Japan Project, Uchio, Y, Kubo, M, Kamatani, Y, Lophatananon, A, Wan, P, Andrews, C, Lori, A, Choudhury, PP, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Rentsch, CT, Cho, K, Mcmahon, BH, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, A, Stroomberg, HV, Batra, J, Chambers, S, Horvath, L, Clements, JA, Tilly, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, S, Cook, MB, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Koutros, S, Beane Freeman, LE, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Butler, EN, Mohler, JL, Taylor, JA, Kogevinas, M, Dierssen-Sotos, T, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Pilie, P, Yu, Y, Bohlender, RJ, Gu, J, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Brenner, H, Chen, X, Holleczek, B, Schöttker, B, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, CM, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Abraham, A, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, J, Petrovics, G, Casey, G, Wang, Y, Tettey, Y, Lachance, J, Tang, W, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Yamoah, K, Govindasami, K, Chokkalingam, AP, Keaton, JM, Hellwege, JN, Clark, PE, Jalloh, M, Gueye, SM, Niang, L, Ogunbiyi, O, Shittu, O, Amodu, O, Adebiyi, AO, Aisuodionoe-Shadrach, OI, Ajibola, HO, Jamda, MA, Oluwole, OP, Nwegbu, M, Adusei, B, Mante, S, Darkwa-Abrahams, A, Diop, H, Gundell, SM, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Kachuri, L, Varma, R, McKean-Cowdin, R, Torres, M, Preuss, MH, Loos, RJF, Zawistowski, M, Zöllner, S, Lu, Z, Van Den Eeden, SK, Easton, DF, Ambs, S, Edwards, TL, Mägi, R, Rebbeck, TR, Fritsche, L, Chanock, SJ, Berndt, SI, Wiklund, F, Nakagawa, H, Witte, JS, Gaziano, JM, Justice, AC, Mancuso, N, Terao, C, Eeles, RA, Kote-Jarai, Z, Madduri, RK, Conti, DV, and Haiman, CA
Abstract: The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
Published: 2023

4. Marital status and prostate cancer incidence: a pooled analysis of 12 case-control studies from the PRACTICAL consortium

Author: Salmon, C, Song, L, Muir, K, UKGPCS Collaborators, Pashayan, N, Dunning, AM, Batra, J, APCB BioResource (Australian Prostate Cancer BioResource), Chambers, S, Stanford, JL, Ostrander, EA, Park, JY, Lin, H-Y, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Cordina-Duverger, E, Kogevinas, M, Llorca, J, Kaneva, R, Slavov, C, Razack, A, Lim, J, Gago-Dominguez, M, Castelao, JE, Kote-Jarai, Z, Eeles, RA, on behalf of the PRACTICAL Consortium, and Parent, M-É
Subjects: Male, Marital Status, Epidemiology, Incidence, Prostatic Neoplasms, Social Support, Single Person, Adenocarcinoma, Middle Aged, 1117 Public Health and Health Services, Divorce, Population Surveillance, Humans, Marriage, Aged
Abstract: While being in a committed relationship is associated with a better prostate cancer prognosis, little is known about how marital status relates to its incidence. Social support provided by marriage/relationship could promote a healthy lifestyle and an increased healthcare seeking behavior. We investigated the association between marital status and prostate cancer risk using data from the PRACTICAL Consortium. Pooled analyses were conducted combining 12 case-control studies based on histologically-confirmed incident prostate cancers and controls with information on marital status prior to diagnosis/interview. Marital status was categorized as married/partner, separated/divorced, single, or widowed. Tumours with Gleason scores ≥ 8 defined high-grade cancers, and low-grade otherwise. NCI-SEER's summary stages (local, regional, distant) indicated the extent of the cancer. Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CI) for the association between marital status and prostate cancer risk, adjusting for potential confounders. Overall, 14,760 cases and 12,019 controls contributed to analyses. Compared to men who were married/with a partner, widowed men had an OR of 1.19 (95% CI 1.03-1.35) of prostate cancer, with little difference between low- and high-grade tumours. Risk estimates among widowers were 1.14 (95% CI 0.97-1.34) for local, 1.53 (95% CI 1.22-1.92) for regional, and 1.56 (95% CI 1.05-2.32) for distant stage tumours. Single men had elevated risks of high-grade cancers. Our findings highlight elevated risks of incident prostate cancer among widowers, more often characterized by tumours that had spread beyond the prostate at the time of diagnosis. Social support interventions and closer medical follow-up in this sub-population are warranted.
Published: 2021

5. Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer

Author: Schaid, DJ, McDonnell, SK, FitzGerald, LM, DeRycke, L, Fogarty, Z, Giles, GG, MacInnis, RJ, Southey, MC, Nguyen-Dumont, T, Cancel-Tassin, G, Cussenot, O, Whittemore, AS, Sieh, W, Ioannidis, NM, Hsieh, C-L, Stanford, JL, Schleutker, J, Cropp, CD, Carpten, J, Hoegel, J, Eeles, R, Kote-Jarai, Z, Ackerman, MJ, Klein, CJ, Mandal, D, Cooney, KA, Bailey-Wilson, JE, Helfand, B, Catalona, WJ, Wiklund, F, Riska, S, Bahetti, S, Larson, MC, Albright, LC, Teerlink, C, Xu, J, Isaacs, W, Ostrander, EA, Thibodeau, SN, Schaid, DJ, McDonnell, SK, FitzGerald, LM, DeRycke, L, Fogarty, Z, Giles, GG, MacInnis, RJ, Southey, MC, Nguyen-Dumont, T, Cancel-Tassin, G, Cussenot, O, Whittemore, AS, Sieh, W, Ioannidis, NM, Hsieh, C-L, Stanford, JL, Schleutker, J, Cropp, CD, Carpten, J, Hoegel, J, Eeles, R, Kote-Jarai, Z, Ackerman, MJ, Klein, CJ, Mandal, D, Cooney, KA, Bailey-Wilson, JE, Helfand, B, Catalona, WJ, Wiklund, F, Riska, S, Bahetti, S, Larson, MC, Albright, LC, Teerlink, C, Xu, J, Isaacs, W, Ostrander, EA, and Thibodeau, SN
Abstract: BACKGROUND: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. OBJECTIVE: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. RESULTS AND LIMITATIONS: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. CONCLUSIONS: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. PATIENT SUMMARY: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.
Published: 2021

6. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author: Conti, D, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Al Olama, AA, Benlloch, S, Dadaev, T, Brook, MN, Sahimi, A, Hoffmann, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Muir, K, Lophatananon, A, Wan, P, Le Marchand, L, Wilkens, LR, Stevens, VL, Gapstur, SM, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Roder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-E, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Hakansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sorensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gomez-Caamano, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandao, A, Watya, S, Lubwama, A, Bensen, JT, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castano-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Berndt, S, Van den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, Haiman, CA, Conti, D, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Al Olama, AA, Benlloch, S, Dadaev, T, Brook, MN, Sahimi, A, Hoffmann, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Muir, K, Lophatananon, A, Wan, P, Le Marchand, L, Wilkens, LR, Stevens, VL, Gapstur, SM, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokolorczyk, D, Lubinski, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Roder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordstrom, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-E, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Hakansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sorensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gomez-Caamano, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandao, A, Watya, S, Lubwama, A, Bensen, JT, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castano-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Berndt, S, Van den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, and Haiman, CA
Abstract: Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
Published: 2021

7. Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study

Author: Karlsson, Q, Brook, MN, Dadaev, T, Wakerell, S, Saunders, EJ, Muir, K, Neal, DE, Giles, GG, MacInnis, RJ, Thibodeau, SN, McDonnell, SK, Cannon-Albright, L, Teixeira, MR, Paulo, P, Cardoso, M, Huff, C, Li, D, Yao, Y, Scheet, P, Permuth, JB, Stanford, JL, Dai, JY, Ostrander, EA, Cussenot, O, Cancel-Tassin, G, Hoegel, J, Herkommer, K, Schleutker, J, Tammela, TLJ, Rathinakannan, V, Sipeky, C, Wiklund, F, Gronberg, H, Aly, M, Isaacs, WB, Dickinson, JL, FitzGerald, LM, Chua, MLK, Nguyen-Dumont, T, Consortium, P, Schaid, DJ, Southey, MC, Eeles, RA, Kote-Jarai, Z, Karlsson, Q, Brook, MN, Dadaev, T, Wakerell, S, Saunders, EJ, Muir, K, Neal, DE, Giles, GG, MacInnis, RJ, Thibodeau, SN, McDonnell, SK, Cannon-Albright, L, Teixeira, MR, Paulo, P, Cardoso, M, Huff, C, Li, D, Yao, Y, Scheet, P, Permuth, JB, Stanford, JL, Dai, JY, Ostrander, EA, Cussenot, O, Cancel-Tassin, G, Hoegel, J, Herkommer, K, Schleutker, J, Tammela, TLJ, Rathinakannan, V, Sipeky, C, Wiklund, F, Gronberg, H, Aly, M, Isaacs, WB, Dickinson, JL, FitzGerald, LM, Chua, MLK, Nguyen-Dumont, T, Consortium, P, Schaid, DJ, Southey, MC, Eeles, RA, and Kote-Jarai, Z
Abstract: BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.
Published: 2021

8. Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author: Conti, DV, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Olama, AAA, Benlloch, S, Dadaev, T, Brook, MN, Sahimi, A, Hoffmann, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Muir, K, Lophatananon, A, Wan, P, Le Marchand, L, Wilkens, LR, Stevens, VL, Gapstur, SM, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokołorczyk, D, Lubiński, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordström, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Berndt, SI, Van Den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, Haiman, CA, Conti, DV, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Olama, AAA, Benlloch, S, Dadaev, T, Brook, MN, Sahimi, A, Hoffmann, TJ, Takahashi, A, Matsuda, K, Momozawa, Y, Fujita, M, Muir, K, Lophatananon, A, Wan, P, Le Marchand, L, Wilkens, LR, Stevens, VL, Gapstur, SM, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokołorczyk, D, Lubiński, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordström, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Berndt, SI, Van Den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, and Haiman, CA
Abstract: In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.
Published: 2021

9. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Author: Conti, DV, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Olama, AAA, Benlloch, S, Dadaev, T, Brook, MN, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Sahimi, A, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Hoffmann, TJ, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Takahashi, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Matsuda, K, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Momozawa, Y, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Fujita, M, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Muir, K, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Lophatananon, A, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Wan, P, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Le Marchand, L, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Wilkens, LR, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Stevens, VL, Berndt, SI, Van Den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, Gapstur, SM, Haiman, CA, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokołorczyk, D, Lubiński, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordström, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, Lu, Y-J, Conti, DV, Darst, BF, Moss, LC, Saunders, EJ, Sheng, X, Chou, A, Schumacher, FR, Olama, AAA, Benlloch, S, Dadaev, T, Brook, MN, Zhang, H-W, Feng, N, Mao, X, Wu, Y, Zhao, S-C, Sun, Z, Thibodeau, SN, McDonnell, SK, Schaid, DJ, West, CML, Sahimi, A, Burnet, N, Barnett, G, Maier, C, Schnoeller, T, Luedeke, M, Kibel, AS, Drake, BF, Cussenot, O, Cancel-Tassin, G, Menegaux, F, Hoffmann, TJ, Truong, T, Koudou, YA, John, EM, Grindedal, EM, Maehle, L, Khaw, K-T, Ingles, SA, Stern, MC, Vega, A, Gómez-Caamaño, A, Takahashi, A, Fachal, L, Rosenstein, BS, Kerns, SL, Ostrer, H, Teixeira, MR, Paulo, P, Brandão, A, Watya, S, Lubwama, A, Bensen, JT, Matsuda, K, Fontham, ETH, Mohler, J, Taylor, JA, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Cannon-Albright, L, Teerlink, CC, Huff, CD, Strom, SS, Momozawa, Y, Multigner, L, Blanchet, P, Brureau, L, Kaneva, R, Slavov, C, Mitev, V, Leach, RJ, Weaver, B, Brenner, H, Cuk, K, Fujita, M, Holleczek, B, Saum, K-U, Klein, EA, Hsing, AW, Kittles, RA, Murphy, AB, Logothetis, CJ, Kim, J, Neuhausen, SL, Steele, L, Muir, K, Ding, YC, Isaacs, WB, Nemesure, B, Hennis, AJM, Carpten, J, Pandha, H, Michael, A, De Ruyck, K, De Meerleer, G, Ost, P, Lophatananon, A, Xu, J, Razack, A, Lim, J, Teo, S-H, Newcomb, LF, Lin, DW, Fowke, JH, Neslund-Dudas, C, Rybicki, BA, Gamulin, M, Wan, P, Lessel, D, Kulis, T, Usmani, N, Singhal, S, Parliament, M, Claessens, F, Joniau, S, Van den Broeck, T, Gago-Dominguez, M, Castelao, JE, Le Marchand, L, Martinez, ME, Larkin, S, Townsend, PA, Aukim-Hastie, C, Bush, WS, Aldrich, MC, Crawford, DC, Srivastava, S, Cullen, JC, Petrovics, G, Wilkens, LR, Casey, G, Roobol, MJ, Jenster, G, van Schaik, RHN, Hu, JJ, Sanderson, M, Varma, R, McKean-Cowdin, R, Torres, M, Mancuso, N, Stevens, VL, Berndt, SI, Van Den Eeden, SK, Easton, DF, Chanock, SJ, Cook, MB, Wiklund, F, Nakagawa, H, Witte, JS, Eeles, RA, Kote-Jarai, Z, Gapstur, SM, Haiman, CA, Carter, BD, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Giles, GG, Southey, MC, MacInnis, RJ, Cybulski, C, Wokołorczyk, D, Lubiński, J, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bojesen, SE, Røder, MA, Iversen, P, Batra, J, Chambers, S, Moya, L, Horvath, L, Clements, JA, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Szulkin, R, Eklund, M, Nordström, T, Pashayan, N, Dunning, AM, Ghoussaini, M, Travis, RC, Key, TJ, Riboli, E, Park, JY, Sellers, TA, Lin, H-Y, Albanes, D, Weinstein, SJ, Mucci, LA, Giovannucci, E, Lindstrom, S, Kraft, P, Hunter, DJ, Penney, KL, Turman, C, Tangen, CM, Goodman, PJ, Thompson, IM, Hamilton, RJ, Fleshner, NE, Finelli, A, Parent, M-É, Stanford, JL, Ostrander, EA, Geybels, MS, Koutros, S, Freeman, LEB, Stampfer, M, Wolk, A, Håkansson, N, Andriole, GL, Hoover, RN, Machiela, MJ, Sørensen, KD, Borre, M, Blot, WJ, Zheng, W, Yeboah, ED, Mensah, JE, and Lu, Y-J
Abstract: Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
Published: 2021

10. Turmeric and Its Major Compound Curcumin on Health: Bioactive Effects and Safety Profiles for Food, Pharmaceutical, Biotechnological and Medicinal Applications.

Author: Sharifi-Rad, J, Rayess, YE, Rizk, AA, Sadaka, C, Zgheib, R, Zam, W, Sestito, S, Rapposelli, S, Neffe-Skocińska, K, Zielińska, D, Salehi, B, Setzer, WN, Dosoky, NS, Taheri, Y, El Beyrouthy, M, Martorell, M, Ostrander, EA, Suleria, HAR, Cho, WC, Maroyi, A, Martins, N, Sharifi-Rad, J, Rayess, YE, Rizk, AA, Sadaka, C, Zgheib, R, Zam, W, Sestito, S, Rapposelli, S, Neffe-Skocińska, K, Zielińska, D, Salehi, B, Setzer, WN, Dosoky, NS, Taheri, Y, El Beyrouthy, M, Martorell, M, Ostrander, EA, Suleria, HAR, Cho, WC, Maroyi, A, and Martins, N
Abstract: Curcumin, a yellow polyphenolic pigment from the Curcuma longa L. (turmeric) rhizome, has been used for centuries for culinary and food coloring purposes, and as an ingredient for various medicinal preparations, widely used in Ayurveda and Chinese medicine. In recent decades, their biological activities have been extensively studied. Thus, this review aims to offer an in-depth discussion of curcumin applications for food and biotechnological industries, and on health promotion and disease prevention, with particular emphasis on its antioxidant, anti-inflammatory, neuroprotective, anticancer, hepatoprotective, and cardioprotective effects. Bioavailability, bioefficacy and safety features, side effects, and quality parameters of curcumin are also addressed. Finally, curcumin's multidimensional applications, food attractiveness optimization, agro-industrial procedures to offset its instability and low bioavailability, health concerns, and upcoming strategies for clinical application are also covered.
Published: 2020

11. Germline variation at 8q24 and prostate cancer risk in men of European ancestry (vol 9, 4616, 2018)

Author: Matejcic, M, Saunders, EJ, Dadaev, T, Brook, MN, Wang, K, Sheng, X, Al Olama, AA, Schumacher, FR, Ingles, SA, Govindasami, K, Benlloch, S, Berndt, SI, Albanes, D, Koutros, S, Muir, K, Stevens, VL, Gapstur, SM, Tangen, CM, Batra, J, Clements, J, Gronberg, H, Pashayan, N, Schleutker, J, Wolk, A, West, C, Mucci, L, Kraft, P, Cancel-Tassin, G, Sorensen, KD, Maehle, L, Grindedal, EM, Strom, SS, Neal, DE, Hamdy, FC, Donovan, JL, Travis, RC, Hamilton, RJ, Rosenstein, B, Lu, Y-J, Giles, GG, Kibel, AS, Vega, A, Bensen, JT, Kogevinas, M, Penney, KL, Park, JY, Stanford, JL, Cybulski, C, Nordestgaard, BG, Brenner, H, Maier, C, Kim, J, Teixeira, MR, Neuhausen, SL, De Ruyck, K, Razack, A, Newcomb, LF, Lessel, D, Kaneva, R, Usmani, N, Claessens, F, Townsend, PA, Gago-Dominguez, M, Roobol, MJ, Menegaux, F, Khaw, K-T, Cannon-Albright, LA, Pandha, H, Thibodeau, SN, Schaid, DJ, Wiklund, F, Chanock, SJ, Easton, DF, Eeles, RA, Kote-Jarai, Z, Conti, DV, Haiman, CA, Henderson, BE, Stern, MC, Thwaites, A, Guy, M, Whitmore, I, Morgan, A, Fisher, C, Hazel, S, Livni, N, Cook, M, Fachal, L, Weinstein, S, Freeman, LEB, Hoover, RN, Machiela, MJ, Lophatananon, A, Carter, BD, Goodman, P, Moya, L, Srinivasan, S, Kedda, M-A, Yeadon, T, Eckert, A, Eklund, M, Cavalli-Bjoerkman, C, Dunning, AM, Sipeky, C, Hakansson, N, Elliott, R, Ranu, H, Giovannucci, E, Turman, C, Hunter, DJ, Cussenot, O, Orntoft, TF, Lane, A, Lewis, SJ, Davis, M, Key, TJ, Brown, P, Kulkarni, GS, Zlotta, AR, Fleshner, NE, Finelli, A, Mao, X, Marzec, J, MacInnis, RJ, Milne, R, Hopper, JL, Aguado, M, Bustamante, M, Castano-Vinyals, G, Gracia-Lavedan, E, Cecchini, L, Stampfer, M, Ma, J, Sellers, TA, Geybels, MS, Park, H, Zachariah, B, Kolb, S, Wokolorczyk, D, Lubinski, J, Kluzniak, W, Nielsen, SF, Weisher, M, Cuk, K, Vogel, W, Luedeke, M, Logothetis, CJ, Paulo, P, Cardoso, M, Maia, S, Silva, MP, Steele, L, Ding, YC, De Meerleer, G, De Langhe, S, Thierens, H, Lim, J, Tan, MH, Ong, AT, Lin, DW, Kachakova, D, Mitkova, A, Mitev, V, Parliament, M, Jenster, G, Bangma, C, Schroder, FH, Truong, T, Koudou, YA, Michael, A, Kierzek, A, Karlsson, A, Broms, M, Wu, H, Aukim-Hastie, C, Tillmans, L, Riska, S, McDonnell, SK, Dearnaley, D, Spurdle, A, Gardiner, R, Hayes, V, Butler, L, Taylor, R, Papargiris, M, Saunders, P, Kujala, P, Talala, K, Taari, K, Bentzen, S, Hicks, B, Vogt, A, Hutchinson, A, Cox, A, George, A, Toi, A, Evans, A, Van der Kwast, TH, Imai, T, Saito, S, Zhao, S-C, Ren, G, Zhang, Y, Yu, Y, Wu, Y, Wu, J, Zhou, B, Pedersen, J, Lobato-Busto, R, Manuel Ruiz-Dominguez, J, Mengual, L, Alcaraz, A, Pow-Sang, J, Herkommer, K, Vlahova, A, Dikov, T, Christova, S, Carracedo, A, Tretarre, B, Rebillard, X, Mulot, C, Adolfsson, J, Stattin, P, Johansson, J-E, Martin, RM, Thompson, IM, Chambers, S, Aitken, J, Horvath, L, Haynes, A-M, Tilley, W, Risbridger, G, Aly, M, Nordstrom, T, Pharoah, P, Tammela, TLJ, Murtola, T, Auvinen, A, Burnet, N, Barnett, G, Andriole, G, Klim, A, Drake, BF, Borre, M, Kerns, S, Ostrer, H, Zhang, H-W, Cao, G, Lin, J, Ling, J, Li, M, Feng, N, Li, J, He, W, Guo, X, Sun, Z, Wang, G, Guo, J, Southey, MC, FitzGerald, LM, Marsden, G, Gomez-Caamano, A, Carballo, A, Peleteiro, P, Calvo, P, Szulkin, R, Llorca, J, Dierssen-Sotos, T, Gomez-Acebo, I, Lin, H-Y, Ostrander, EA, Bisbjerg, R, Klarskov, P, Roder, MA, Iversen, P, Holleczek, B, Stegmaier, C, Schnoeller, T, Bohnert, P, John, EM, Ost, P, Teo, S-H, Gamulin, M, Kulis, T, Kastelan, Z, Slavov, C, Popov, E, Van den Broeck, T, Joniau, S, Larkin, S, Esteban Castelao, J, Martinez, ME, Van Schaik, RHN, Xu, J, Lindstrom, S, Riboli, E, Berry, C, Siddiq, A, Canzian, F, Kolonel, LN, Le Marchand, L, Freedman, M, Cenee, S, Sanchez, M, and Commission of the European Communities
Subjects: Multidisciplinary Sciences, Science & Technology, MD Multidisciplinary, Science & Technology - Other Topics, PRACTICAL Consortium
Abstract: Correction to: Nature Communications; https://doi.org/10.1038/s41467-018-06863-1, published online 5 November 2018.
Published: 2019

12. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Author: Dadaev, T, Saunders, EJ, Newcombe, PJ, Anokian, E, Leongamornlert, DA, Brook, MN, Cieza-Borrella, C, Mijuskovic, M, Wakerell, S, Olama, AAA, Schumacher, FR, Berndt, SI, Benlloch, S, Ahmed, M, Goh, C, Sheng, X, Zhang, Z, Muir, K, Govindasami, K, Lophatananon, A, Stevens, VL, Gapstur, SM, Carter, BD, Tangen, CM, Goodman, P, Thompson, IM, Batra, J, Chambers, S, Moya, L, Clements, J, Horvath, L, Tilley, W, Risbridger, G, Gronberg, H, Aly, M, Nordström, T, Pharoah, P, Pashayan, N, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Albanes, D, Weinstein, S, Wolk, A, Hakansson, N, West, C, Dunning, AM, Burnet, N, Mucci, L, Giovannucci, E, Andriole, G, Cussenot, O, Cancel-Tassin, G, Koutros, S, Freeman, LEB, Sorensen, KD, Orntoft, TF, Borre, M, Maehle, L, Grindedal, EM, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Travis, RC, Key, TJ, Hamilton, RJ, Fleshner, NE, Finelli, A, Ingles, SA, Stern, MC, Rosenstein, B, Kerns, S, Ostrer, H, Lu, Y-J, Zhang, H-W, Feng, N, Mao, X, Guo, X, Wang, G, Sun, Z, Giles, GG, Southey, MC, Macinnis, RJ, Fitzgerald, LM, Kibel, AS, Drake, BF, Vega, A, Gómez-Caamaño, A, Fachal, L, Szulkin, R, Eklund, M, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Penney, KL, Stampfer, M, Park, JY, Sellers, TA, Lin, H-Y, Stanford, JL, Cybulski, C, Wokolorczyk, D, Lubinski, J, Ostrander, EA, Geybels, MS, Nordestgaard, BG, Nielsen, SF, Weisher, M, Bisbjerg, R, Røder, MA, Iversen, P, Brenner, H, Cuk, K, Holleczek, B, Maier, C, Luedeke, M, Schnoeller, T, Kim, J, Logothetis, CJ, John, EM, Teixeira, MR, Paulo, P, Cardoso, M, Neuhausen, SL, Steele, L, Ding, YC, De Ruyck, K, De Meerleer, G, Ost, P, Razack, A, Lim, J, Teo, S-H, Lin, DW, Newcomb, LF, Lessel, D, Gamulin, M, Kulis, T, Kaneva, R, Usmani, N, Slavov, C, Mitev, V, Parliament, M, Singhal, S, Claessens, F, Joniau, S, Van Den Broeck, T, Larkin, S, Townsend, PA, Aukim-Hastie, C, Gago-Dominguez, M, Castelao, JE, Martinez, ME, Roobol, MJ, Jenster, G, Van Schaik, RHN, Menegaux, F, Truong, T, Koudou, YA, Xu, J, Khaw, K-T, Cannon-Albright, L, Pandha, H, Michael, A, Kierzek, A, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Lindstrom, S, Turman, C, Ma, J, Hunter, DJ, Riboli, E, Siddiq, A, Canzian, F, Kolonel, LN, Le Marchand, L, Hoover, RN, Machiela, MJ, Kraft, P, Consortium, Practical (Prostate Cancer Association Group To Investigate Cancer-Associated Alterations In The Genome), Freedman, M, Wiklund, F, Chanock, S, Henderson, BE, Easton, DF, Haiman, CA, Eeles, RA, Conti, DV, Kote-Jarai, Z, Dadaev, Tokhir [0000-0002-8268-0438], Leongamornlert, Daniel A [0000-0002-3486-3168], Brook, Mark N [0000-0002-8969-2378], Olama, Ali Amin Al [0000-0002-7178-3431], Schumacher, Fredrick R [0000-0002-3073-7463], Muir, Kenneth [0000-0001-6429-988X], Batra, Jyotsna [0000-0003-4646-6247], Nordström, Tobias [0000-0003-4915-7546], Pharoah, Paul [0000-0001-8494-732X], Pashayan, Nora [0000-0003-0843-2468], Schleutker, Johanna [0000-0002-1863-0305], Sipeky, Csilla [0000-0002-8853-4722], Wolk, Alicja [0000-0001-7387-6845], Cancel-Tassin, Géraldine [0000-0002-9583-6382], Sorensen, Karina Dalsgaard [0000-0002-4902-5490], Kerns, Sarah [0000-0002-6503-0011], Ostrer, Harry [0000-0002-2209-5376], Fachal, Laura [0000-0002-7256-9752], Kogevinas, Manolis [0000-0002-9605-0461], Nordestgaard, Børge G [0000-0002-1954-7220], Lim, Jasmine [0000-0002-7501-1834], Truong, Thérèse [0000-0002-2943-6786], Xu, Jianfeng [0000-0002-1343-8752], Easton, Douglas F [0000-0003-2444-3247], Eeles, Rosalind A [0000-0002-3698-6241], Apollo - University of Cambridge Repository, National Institutes of Health, Urology, and Clinical Chemistry
Subjects: Male, Risk, Science, GENETIC, Quantitative Trait Loci, Black People, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, urologic and male genital diseases, ANNOTATION, Polymorphism, Single Nucleotide, Article, White People, REGION, GENETIC ASSOCIATION, SDG 3 - Good Health and Well-being, MD Multidisciplinary, Medicine and Health Sciences, ELEMENTS, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, lcsh:Science, Medicinsk genetik, MODEL SELECTION, BAYESIAN FRAMEWORK, Cancer och onkologi, Science & Technology, Chromosome Mapping, Prostatic Neoplasms, Bayes Theorem, Molecular Sequence Annotation, ASSOCIATION, JOINT ANALYSIS, RISK LOCI, STATISTICS, Multidisciplinary Sciences, Cancer and Oncology, Multivariate Analysis, Science & Technology - Other Topics, lcsh:Q, Medical Genetics, Algorithms, VARIABLE-SELECTION, Genome-Wide Association Study
Abstract: Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling., Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.
Published: 2018

13. Germline variants in IL4, MGMT and AKT1 are associated with prostate cancer-specific mortality: An analysis of 12,082 prostate cancer cases

Author: FitzGerald, LM, Zhao, S, Leonardson, A, Geybels, MS, Kolb, S, Lin, DW, Wright, JL, Eeles, R, Kote-Jarai, Z, Govindasami, K, Giles, GG, Southey, MC, Schleutker, J, Tammela, TL, Sipeky, C, Penney, KL, Stampfer, MJ, Gronberg, H, Wiklund, F, Stattin, P, Hugosson, J, Karyadi, DM, Ostrander, EA, Feng, Z, Stanford, JL, FitzGerald, LM, Zhao, S, Leonardson, A, Geybels, MS, Kolb, S, Lin, DW, Wright, JL, Eeles, R, Kote-Jarai, Z, Govindasami, K, Giles, GG, Southey, MC, Schleutker, J, Tammela, TL, Sipeky, C, Penney, KL, Stampfer, MJ, Gronberg, H, Wiklund, F, Stattin, P, Hugosson, J, Karyadi, DM, Ostrander, EA, Feng, Z, and Stanford, JL
Abstract: BACKGROUND: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. METHODS: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.
Published: 2018

14. Rare, protein-truncating variants in $\textit{ATM}$, $\textit{CHEK2}$ and $\textit{PALB2}$, but not $\textit{XRCC2}$, are associated with increased breast cancer risks

Author: Decker, B, Allen, J, Luccarini, C, Pooley, KA, Shah, M, Bolla, MK, Wang, Q, Ahmed, S, Baynes, C, Conroy, DM, Brown, J, Luben, R, Ostrander, EA, Pharoah, PD, Dunning, AM, Easton, DF, Allen, Jamie [0000-0002-8677-2225], Pooley, Karen [0000-0002-1274-9460], Wang, Jean [0000-0002-9139-0627], Luben, Robert [0000-0002-5088-6343], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Cancer: breast, Genetic Variation, Breast Neoplasms, Ataxia Telangiectasia Mutated Proteins, DNA-Binding Proteins, Checkpoint Kinase 2, Evidence Based Practice, Sequence Analysis, Protein, Genetic Epidemiology, Humans, Female, Genetic Predisposition to Disease, Fanconi Anemia Complementation Group N Protein, Geneticscreening/counselling
Abstract: BACKGROUND: Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK. METHODS: Gene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four in silico algorithms. RESULTS: Truncating variants in PALB2 (OR=4.69, 95% CI 2.27 to 9.68), ATM (OR=3.26; 95% CI 1.82 to 6.46) and CHEK2 (OR=3.11; 95% CI 2.15 to 4.69), but not XRCC2 (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in ATM and CHEK2 were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in PALB2 were associated with similar risks for both subtypes. There was also some evidence that missense variants in ATM, CHEK2 and PALB2 may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect. CONCLUSIONS: Truncating variants in PALB2 are associated with a higher risk of BC than those in ATM or CHEK2. A substantial risk of BC due to truncating XRCC2 variants can be excluded.
Published: 2017
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15. gsSKAT: Rapid gene set analysis and multiple testing correction for rare-variant association studies using weighted linear kernels

Author: Larson, NB, McDonnell, S, Albright, LC, Teerlink, C, Stanford, J, Ostrander, EA, Isaacs, WB, Xu, J, Cooney, KA, Lange, E, Schleutker, J, Carpten, JD, Powell, I, Bailey-Wilson, JE, Cussenot, O, Cancel-Tassin, G, Giles, GG, MacInnis, RJ, Maier, C, Whittemore, AS, Hsieh, C-L, Wiklund, F, Catolona, WJ, Foulkes, W, Mandal, D, Eeles, R, Kote-Jarai, Z, Ackerman, MJ, Olson, TM, Klein, CJ, Thibodeau, SN, Schaid, DJ, Larson, NB, McDonnell, S, Albright, LC, Teerlink, C, Stanford, J, Ostrander, EA, Isaacs, WB, Xu, J, Cooney, KA, Lange, E, Schleutker, J, Carpten, JD, Powell, I, Bailey-Wilson, JE, Cussenot, O, Cancel-Tassin, G, Giles, GG, MacInnis, RJ, Maier, C, Whittemore, AS, Hsieh, C-L, Wiklund, F, Catolona, WJ, Foulkes, W, Mandal, D, Eeles, R, Kote-Jarai, Z, Ackerman, MJ, Olson, TM, Klein, CJ, Thibodeau, SN, and Schaid, DJ
Abstract: Next-generation sequencing technologies have afforded unprecedented characterization of low-frequency and rare genetic variation. Due to low power for single-variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel-machine regression and adaptive testing methods for aggregative rare-variant association testing have been demonstrated to be powerful approaches for pathway-level analysis, although these methods tend to be computationally intensive at high-variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare-variant analysis using component gene-level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family-wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case-control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open-source R code for public use to facilitate easy application of our methods to existing rare-variant analysis results.
Published: 2017

16. Out of the dog house: the emergence of the canine genome

Author: Wayne, RK and Ostrander, EA
Subjects: Human genetics -- Research, Nucleotide sequence -- Research, Biological sciences
Abstract: An attempt is made to review the recent progress in the genome sequencing of the dog and discuss new discoveries based on its comparison to mouse and human. Also, current efforts to complete the dog genome and the promise that this holds for comparative genomic and evolutionary studies are overviewed.
Published: 2004

17. Two susceptibility loci identified for prostate cancer aggressiveness

Author: Berndt, Si, Wang, Z, Yeager, M, Alavanja, Mc, Albanes, D, Amundadottir, L, Andriole, G, Beane Freeman, L, Campa, D, Cancel-Tassin, G, Canzian, F, Cornu, Jn, Cussenot, O, Diver, Wr, Gapstur, Sm, Grönberg, H, Haiman, Ca, Henderson, B, Hutchinson, A, Hunter, Dj, Key, Tj, Kolb, S, Koutros, S, Kraft, P, Le Marchand, L, Lindström, S, Machiela, Mj, Ostrander, Ea, Riboli, E, Schumacher, F, Siddiq, A, Stanford, Jl, Stevens, Vl, Travis, Rc, Tsilidis, Kk, Virtamo, J, Weinstein, S, Wilkund, F, Xu, J, Lilly Zheng, S, Yu, K, Wheeler, W, Zhang, H, African, Ancestry Prostate Cancer GWAS Consortium, Sampson, J, Black, A, Jacobs, K, Hoover, Rn, Tucker, M, Chanock, Sj. Ingles SA, Kittles, Ra, Strom, Ss, Rybicki, Ba, Nemesure, B, Isaacs, Wb, Zheng, W, Pettaway, Ca, Yeboah, Ed, Tettey, Y, Biritwum, Rb, Adjei, Aa, Tay, E, Truelove, A, Niwa, S, Chokkalingam, Ap, John, Em, Murphy, Ab, Signorello, Lb, Carpten, J, Leske, Mc, Wu, Sy, Hennis, Aj, Neslund-Dudas, C, Hsing, Aw, Chu, L, Goodman, Pj, Klein, Ea, Witte, Js, Casey, G, Kaggwa, S, Cook, Mb, Stram, Do, and Blot, Wj.
Subjects: Oncology, Male, Aging, GLEASON SCORE, LINKAGE SCAN, General Physics and Astronomy, Genome-wide association study, Disease, Bioinformatics, Prostate cancer, SEQUENCE VARIANTS, Medicine, 2.1 Biological and endogenous factors, GTPASE-ACTIVATING PROTEIN, Aetiology, POPULATION, Cancer, RISK, education.field_of_study, African Ancestry Prostate Cancer GWAS Consortium, Multidisciplinary, Prostate Cancer, 3. Good health, Multidisciplinary Sciences, Science & Technology - Other Topics, Urologic Diseases, medicine.medical_specialty, Population, Article, General Biochemistry, Genetics and Molecular Biology, GENOME-WIDE ASSOCIATION, BASE-LINE CHARACTERISTICS, COHORT, METAANALYSIS, Internal medicine, Genetics, SNP, Humans, Neoplasm Invasiveness, Genetic Predisposition to Disease, education, Pathological, Science & Technology, business.industry, Vascular disease, Prevention, Human Genome, Case-control study, Prostatic Neoplasms, General Chemistry, medicine.disease, Genetic Loci, Case-Control Studies, Neoplasm Grading, business
Abstract: Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 × 10(-9)) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 × 10(-8)). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 × 10(-5)) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.
Published: 2015

18. Post hoc Analysis for Detecting Individual Rare Variant Risk Associations Using Probit Regression Bayesian Variable Selection Methods in Case-Control Sequencing Studies

Author: Larson, NB, McDonnell, S, Albright, LC, Teerlink, C, Stanford, J, Ostrander, EA, Isaacs, WB, Xu, J, Cooney, KA, Lange, E, Schleutker, J, Carpten, JD, Powell, I, Bailey-Wilson, J, Cussenot, O, Cancel-Tassin, G, Giles, G, MacInnis, R, Maier, C, Whittemore, AS, Hsieh, C-L, Wiklund, F, Catolona, WJ, Foulkes, W, Mandal, D, Eeles, R, Kote-Jarai, Z, Ackerman, MJ, Olson, TM, Klein, CJ, Thibodeau, SN, Schaid, DJ, Larson, NB, McDonnell, S, Albright, LC, Teerlink, C, Stanford, J, Ostrander, EA, Isaacs, WB, Xu, J, Cooney, KA, Lange, E, Schleutker, J, Carpten, JD, Powell, I, Bailey-Wilson, J, Cussenot, O, Cancel-Tassin, G, Giles, G, MacInnis, R, Maier, C, Whittemore, AS, Hsieh, C-L, Wiklund, F, Catolona, WJ, Foulkes, W, Mandal, D, Eeles, R, Kote-Jarai, Z, Ackerman, MJ, Olson, TM, Klein, CJ, Thibodeau, SN, and Schaid, DJ
Abstract: Rare variants (RVs) have been shown to be significant contributors to complex disease risk. By definition, these variants have very low minor allele frequencies and traditional single-marker methods for statistical analysis are underpowered for typical sequencing study sample sizes. Multimarker burden-type approaches attempt to identify aggregation of RVs across case-control status by analyzing relatively small partitions of the genome, such as genes. However, it is generally the case that the aggregative measure would be a mixture of causal and neutral variants, and these omnibus tests do not directly provide any indication of which RVs may be driving a given association. Recently, Bayesian variable selection approaches have been proposed to identify RV associations from a large set of RVs under consideration. Although these approaches have been shown to be powerful at detecting associations at the RV level, there are often computational limitations on the total quantity of RVs under consideration and compromises are necessary for large-scale application. Here, we propose a computationally efficient alternative formulation of this method using a probit regression approach specifically capable of simultaneously analyzing hundreds to thousands of RVs. We evaluate our approach to detect causal variation on simulated data and examine sensitivity and specificity in instances of high RV dimensionality as well as apply it to pathway-level RV analysis results from a prostate cancer (PC) risk case-control sequencing study. Finally, we discuss potential extensions and future directions of this work.
Published: 2016

19. Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer

Author: Gibson, G, Saunders, EJ, Dadaev, T, Leongamornlert, DA, Jugurnauth-Little, S, Tymrakiewicz, M, Wiklund, F, Al Olama, AA, Benlloch, S, Neal, DE, Hamdy, FC, Donovan, JL, Giles, GG, Severi, G, Gronberg, H, Aly, M, Haiman, CA, Schumacher, F, Henderson, BE, Lindstrom, S, Kraft, P, Hunter, DJ, Gapstur, S, Chanock, S, Berndt, SI, Albanes, D, Andriole, G, Schleutker, J, Weischer, M, Nordestgaard, BG, Canzian, F, Campa, D, Riboli, E, Key, TJ, Travis, RC, Ingles, SA, John, EM, Hayes, RB, Pharoah, P, Khaw, K-T, Stanford, JL, Ostrander, EA, Signorello, LB, Thibodeau, SN, Schaid, D, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, JY, Kaneva, R, Batra, J, Clements, JA, Teixeira, MR, Xu, J, Mikropoulos, C, Goh, C, Govindasami, K, Guy, M, Wilkinson, RA, Sawyer, EJ, Morgan, A, Easton, DF, Muir, K, Eeles, RA, Kote-Jarai, Z, Gibson, G, Saunders, EJ, Dadaev, T, Leongamornlert, DA, Jugurnauth-Little, S, Tymrakiewicz, M, Wiklund, F, Al Olama, AA, Benlloch, S, Neal, DE, Hamdy, FC, Donovan, JL, Giles, GG, Severi, G, Gronberg, H, Aly, M, Haiman, CA, Schumacher, F, Henderson, BE, Lindstrom, S, Kraft, P, Hunter, DJ, Gapstur, S, Chanock, S, Berndt, SI, Albanes, D, Andriole, G, Schleutker, J, Weischer, M, Nordestgaard, BG, Canzian, F, Campa, D, Riboli, E, Key, TJ, Travis, RC, Ingles, SA, John, EM, Hayes, RB, Pharoah, P, Khaw, K-T, Stanford, JL, Ostrander, EA, Signorello, LB, Thibodeau, SN, Schaid, D, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, JY, Kaneva, R, Batra, J, Clements, JA, Teixeira, MR, Xu, J, Mikropoulos, C, Goh, C, Govindasami, K, Guy, M, Wilkinson, RA, Sawyer, EJ, Morgan, A, Easton, DF, Muir, K, Eeles, RA, and Kote-Jarai, Z
Abstract: The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
Published: 2014

20. Genetics of Malignant Histiocytosis in the Bernese Mountain Dog

Author: Cadieu, E, Hedan, B, Parker H, G, Rutteman, Gr, Baffoe-Bonnie, A, Devauchelle, P, Mosher, D, Hitte, Christophe, Badie, J, Deshmukh, S, Galibert, Francis, Breen, Marie, Andre, C, Ostrander, Ea, Inconnu, and ProdInra, Migration
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Published: 2006

21. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Author: Kote-Jarai, Z, Saunders, EJ, Leongamornlert, DA, Tymrakiewicz, M, Dadaev, T, Jugurnauth-Little, S, Ross-Adams, H, Al Olama, AA, Benlloch, S, Halim, S, Russel, R, Dunning, AM, Luccarini, C, Dennis, J, Neal, DE, Hamdy, FC, Donovan, JL, Muir, K, Giles, GG, Severi, G, Wiklund, F, Gronberg, H, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Lindstrom, S, Kraft, P, Hunter, DJ, Gapstur, S, Chanock, S, Berndt, SI, Albanes, D, Andriole, G, Schleutker, J, Weischer, M, Canzian, F, Riboli, E, Key, TJ, Travis, RC, Campa, D, Ingles, SA, John, EM, Hayes, RB, Pharoah, P, Khaw, K-T, Stanford, JL, Ostrander, EA, Signorello, LB, Thibodeau, SN, Schaid, D, Maier, C, Vogel, W, Kibel, AS, Cybulski, C, Lubinski, J, Cannon-Albright, L, Brenner, H, Park, JY, Kaneva, R, Batra, J, Spurdle, A, Clements, JA, Teixeira, MR, Govindasami, K, Guy, M, Wilkinson, RA, Sawyer, EJ, Morgan, A, Dicks, E, Baynes, C, Conroy, D, Bojesen, SE, Kaaks, R, Vincent, D, Bacot, F, Tessier, DC, Easton, DF, Eeles, RA, Kote-Jarai, Z, Saunders, EJ, Leongamornlert, DA, Tymrakiewicz, M, Dadaev, T, Jugurnauth-Little, S, Ross-Adams, H, Al Olama, AA, Benlloch, S, Halim, S, Russel, R, Dunning, AM, Luccarini, C, Dennis, J, Neal, DE, Hamdy, FC, Donovan, JL, Muir, K, Giles, GG, Severi, G, Wiklund, F, Gronberg, H, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Lindstrom, S, Kraft, P, Hunter, DJ, Gapstur, S, Chanock, S, Berndt, SI, Albanes, D, Andriole, G, Schleutker, J, Weischer, M, Canzian, F, Riboli, E, Key, TJ, Travis, RC, Campa, D, Ingles, SA, John, EM, Hayes, RB, Pharoah, P, Khaw, K-T, Stanford, JL, Ostrander, EA, Signorello, LB, Thibodeau, SN, Schaid, D, Maier, C, Vogel, W, Kibel, AS, Cybulski, C, Lubinski, J, Cannon-Albright, L, Brenner, H, Park, JY, Kaneva, R, Batra, J, Spurdle, A, Clements, JA, Teixeira, MR, Govindasami, K, Guy, M, Wilkinson, RA, Sawyer, EJ, Morgan, A, Dicks, E, Baynes, C, Conroy, D, Bojesen, SE, Kaaks, R, Vincent, D, Bacot, F, Tessier, DC, Easton, DF, and Eeles, RA
Abstract: Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.
Published: 2013

22. HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG)

Author: Xu, J, Lange, EM, Lu, L, Zheng, SL, Wang, Z, Thibodeau, SN, Cannon-Albright, LA, Teerlink, CC, Camp, NJ, Johnson, AM, Zuhlke, KA, Stanford, JL, Ostrander, EA, Wiley, KE, Isaacs, SD, Walsh, PC, Maier, C, Luedeke, M, Vogel, W, Schleutker, J, Wahlfors, T, Tammela, T, Schaid, D, McDonnell, SK, DeRycke, MS, Cancel-Tassin, G, Cussenot, O, Wiklund, F, Gronberg, H, Eeles, R, Easton, D, Kote-Jarai, Z, Whittemore, AS, Hsieh, C-L, Giles, GG, Hopper, JL, Severi, G, Catalona, WJ, Mandal, D, Ledet, E, Foulkes, WD, Hamel, N, Mahle, L, Moller, P, Powell, I, Bailey-Wilson, JE, Carpten, JD, Seminara, D, Cooney, KA, Isaacs, WB, Xu, J, Lange, EM, Lu, L, Zheng, SL, Wang, Z, Thibodeau, SN, Cannon-Albright, LA, Teerlink, CC, Camp, NJ, Johnson, AM, Zuhlke, KA, Stanford, JL, Ostrander, EA, Wiley, KE, Isaacs, SD, Walsh, PC, Maier, C, Luedeke, M, Vogel, W, Schleutker, J, Wahlfors, T, Tammela, T, Schaid, D, McDonnell, SK, DeRycke, MS, Cancel-Tassin, G, Cussenot, O, Wiklund, F, Gronberg, H, Eeles, R, Easton, D, Kote-Jarai, Z, Whittemore, AS, Hsieh, C-L, Giles, GG, Hopper, JL, Severi, G, Catalona, WJ, Mandal, D, Ledet, E, Foulkes, WD, Hamel, N, Mahle, L, Moller, P, Powell, I, Bailey-Wilson, JE, Carpten, JD, Seminara, D, Cooney, KA, and Isaacs, WB
Abstract: Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.
Published: 2013

23. Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

Author: Bailey-Wilson, JE, Childs, EJ, Cropp, CD, Schaid, DJ, Xu, J, Camp, NJ, Cannon-Albright, LA, Farnham, JM, George, A, Powell, I, Carpten, JD, Giles, GG, Hopper, JL, Severi, G, English, DR, Foulkes, WD, Maehle, L, Moller, P, Eeles, R, Easton, D, Guy, M, Edwards, S, Badzioch, MD, Whittemore, AS, Oakley-Girvan, I, Hsieh, C-L, Dimitrov, L, Stanford, JL, Karyadi, DM, Deutsch, K, McIntosh, L, Ostrander, EA, Wiley, KE, Isaacs, SD, Walsh, PC, Thibodeau, SN, McDonnell, SK, Hebbring, S, Lange, EM, Cooney, KA, Tammela, TLJ, Schleutker, J, Maier, C, Bochum, S, Hoegel, J, Gronberg, H, Wiklund, F, Emanuelsson, M, Cancel-Tassin, G, Valeri, A, Cussenot, O, Isaacs, WB, Bailey-Wilson, JE, Childs, EJ, Cropp, CD, Schaid, DJ, Xu, J, Camp, NJ, Cannon-Albright, LA, Farnham, JM, George, A, Powell, I, Carpten, JD, Giles, GG, Hopper, JL, Severi, G, English, DR, Foulkes, WD, Maehle, L, Moller, P, Eeles, R, Easton, D, Guy, M, Edwards, S, Badzioch, MD, Whittemore, AS, Oakley-Girvan, I, Hsieh, C-L, Dimitrov, L, Stanford, JL, Karyadi, DM, Deutsch, K, McIntosh, L, Ostrander, EA, Wiley, KE, Isaacs, SD, Walsh, PC, Thibodeau, SN, McDonnell, SK, Hebbring, S, Lange, EM, Cooney, KA, Tammela, TLJ, Schleutker, J, Maier, C, Bochum, S, Hoegel, J, Gronberg, H, Wiklund, F, Emanuelsson, M, Cancel-Tassin, G, Valeri, A, Cussenot, O, and Isaacs, WB
Abstract: BACKGROUND: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive. METHODS: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed. RESULTS: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded. CONCLUSIONS: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. O
Published: 2012

24. Identification, replication, and fine-mapping of loci associated with adult height in individuals of African ancestry

Author: N'Diaye, A, Chen, GK, Palmer, CD, Ge, B, Tayo, B, Mathias, RA, Ding, J, Nalls, MA, Adeyemo, A, Adoue, V, Ambrosone, CB, Atwood, L, Bandera, EV, Becker, LC, Berndt, SI, Bernstein, L, Blot, WJ, Boerwinkle, E, Britton, A, Casey, G, Chanock, SJ, Demerath, E, Deming, SL, Diver, WR, Fox, C, Harris, TB, Hernandez, DG, Hu, JJ, Ingles, SA, John, EM, Johnson, C, Keating, B, Kittles, RA, Kolonel, LN, Kritchevsky, SB, Marchand, L, Lohman, K, Liu, J, Millikan, RC, Murphy, A, Musani, S, Neslund-Dudas, C, North, KE, Nyante, S, Ogunniyi, A, Ostrander, EA, Papanicolaou, G, Patel, S, Pettaway, CA, Press, MF, Redline, S, Rodriguez-Gil, JL, Rotimi, C, Rybicki, BA, Salako, B, Schreiner, PJ, Signorello, LB, Singleton, AB, Stanford, JL, Stram, AH, Stram, DO, Strom, SS, Suktitipat, B, Thun, MJ, Witte, JS, Yanek, LR, Ziegler, RG, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Evans, MK, Liu, Y, Becker, DM, Cooper, RS, Pastinen, T, Henderson, BE, Hirschhorn, JN, Lettre, G, Haiman, CA, N'Diaye, A, Chen, GK, Palmer, CD, Ge, B, Tayo, B, Mathias, RA, Ding, J, Nalls, MA, Adeyemo, A, Adoue, V, Ambrosone, CB, Atwood, L, Bandera, EV, Becker, LC, Berndt, SI, Bernstein, L, Blot, WJ, Boerwinkle, E, Britton, A, Casey, G, Chanock, SJ, Demerath, E, Deming, SL, Diver, WR, Fox, C, Harris, TB, Hernandez, DG, Hu, JJ, Ingles, SA, John, EM, Johnson, C, Keating, B, Kittles, RA, Kolonel, LN, Kritchevsky, SB, Marchand, L, Lohman, K, Liu, J, Millikan, RC, Murphy, A, Musani, S, Neslund-Dudas, C, North, KE, Nyante, S, Ogunniyi, A, Ostrander, EA, Papanicolaou, G, Patel, S, Pettaway, CA, Press, MF, Redline, S, Rodriguez-Gil, JL, Rotimi, C, Rybicki, BA, Salako, B, Schreiner, PJ, Signorello, LB, Singleton, AB, Stanford, JL, Stram, AH, Stram, DO, Strom, SS, Suktitipat, B, Thun, MJ, Witte, JS, Yanek, LR, Ziegler, RG, Zheng, W, Zhu, X, Zmuda, JM, Zonderman, AB, Evans, MK, Liu, Y, Becker, DM, Cooper, RS, Pastinen, T, Henderson, BE, Hirschhorn, JN, Lettre, G, and Haiman, CA
Abstract: Adult height is a classic polygenic trait of high heritability (h 2 ~0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ~10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10 -12 and 2p14-rs4315565, P = 1.2×10 -8). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10 -4 for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits. © 2011 N'Diaye et al.
Published: 2011

25. Development of a clonality assay for canine hematopoietic stem cells [letter]

Author: Wagner, LA, primary, Kiem, HP, additional, McSweeney, P, additional, Schuening, FG, additional, Storb, R, additional, and Ostrander, EA, additional
Published: 1995
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26. BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history.

Author: Malone KE, Daling JR, Thompson JD, O'Brien CA, Francisco LV, Ostrander EA, Malone, K E, Daling, J R, Thompson, J D, O'Brien, C A, Francisco, L V, and Ostrander, E A
Abstract: Context: Studies of high-risk families with multiple early-onset cases of breast cancer have been useful for assessing the type and spectrum of germline mutations on the BRCA1 gene, but do not provide guidance to women with modest family history profiles. Thus, studies of women from the general population are needed to determine the BRCA1 mutation frequency in women perceived to be at high risk, and to develop profiles of those most likely to be carriers.Objective: To characterize frequency and spectrum of germline BRCA1 mutations in 2 categories of women identified via population-based studies hypothesized to be at increased risk of carrying such mutations: those diagnosed as having breast cancer before age 35 years and those diagnosed before age 45 years who have first-degree breast cancer family history.Design: Study subjects were drawn from 2 population-based case-control studies of breast cancer in young women on the basis of their family history or their age of diagnosis. Cases were younger than 35 years or were younger than 45 years with first-degree family history at the time of breast cancer diagnosis and were ascertained via a population-based cancer registry, and controls (women without breast cancer) were identified via random-digit dialing.Setting: Three counties in western Washington State.Main Outcome Measure: BRCA1 germline mutations in study subjects identified in DNA from peripheral blood lymphocytes by single-strand conformation polymorphism analysis using primer pairs that span the BRCA1 coding region and intron-exon boundaries.Results: Of 193 women diagnosed as having breast cancer before age 35 years, none of whom were selected on the basis of family history status, 12 (6.2%, 95% confidence interval [CI], 3.2%-10.6%) had germline BRCA1 mutations. In 208 women diagnosed before age 45 years who had first-degree breast cancer family history, 15 (7.2%, 95% CI,4.1%-11.6%) had germline mutations in BRCA1. In both groups, there were variations in mutation frequency noted by age and by family history. Mutation frequency decreased with increasing age of diagnosis. Higher proportions of mutations were seen in cases with at least 1 relative diagnosed as having breast cancer before age 45 years, in cases with greater numbers of affected relatives, and those with ovarian cancer family history. Mutation frequency did not vary by bilateral breast cancer family history. No frameshift or nonsense mutations were observed in 71 control women with a first-degree family history, although missense changes of unknown significance were seen in cases and controls.Conclusions: Women with BRCA1 germline mutations lacked a common family history profile. Also, a large proportion of the women with a first-degree breast cancer family history and women diagnosed as having breast cancer before age 35 years did not carry germline BRCA1 mutations. Hence, while early-onset disease and a strong breast cancer family history may be useful guidelines for checking BRCA1 status, these findings on women drawn from the general population suggest that it may be difficult to develop BRCA1 mutation screening criteria among women with modest family history profiles. [ABSTRACT FROM AUTHOR]
Published: 1998
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27. Androgen metabolism and JAK/STAT pathway genes and prostate cancer risk.

Author: Kwon EM, Holt SK, Fu R, Kolb S, Williams G, Stanford JL, Ostrander EA, Kwon, Erika M, Holt, Sarah K, Fu, Rong, Kolb, Suzanne, Williams, Gabrielle, Stanford, Janet L, and Ostrander, Elaine A
Abstract: Background: Prostate cancer (PC) is the most frequently diagnosed solid tumor in U.S. men. Genome-wide association studies (GWAS) have identified over 40 risk-associated single nucleotide polymorphisms (SNPs), including variants in androgen pathway genes (e.g., KLK3 and AR). Androgens are important in PC and genes involved in this pathway are therefore candidates for conferring susceptibility to PC.Methods: In this hypothesis-testing study, we evaluated PC risk in association with SNPs in 22 candidate genes involved in androgen metabolism or interactions with the androgen receptor (AR). A total of 187 SNPs were genotyped in 1458 cases and 1351 age-matched controls from a population-based study. PC risk was estimated using adjusted unconditional logistic regression and multinomial regression models.Results: Single SNP analyses showed evidence (p < 0.05) for associations with 14 SNPs in 9 genes: NKX3.1, HSD17B3, AKR1C3, SULT2A1, CYP17A1, KLK3, JAK2, NCOA4 and STAT3. The most significant result was observed for rs2253502 in HSD17B3 (odds ratio, OR = 0.57, 95% CI: 0.39-0.84). In addition, five SNPs in four genes (CYP17A1, HSD17B4, NCOA4, and SULT2A1) were associated with more aggressive disease (p < 0.01).Conclusions: Our results replicate previously reported associations for SNPs in CYP17A1, HSD17B3, ARK1C3, NKX3.1, NCOA4 and KLK3. In addition, novel associations were observed for SNPs in JAK2, HSD17B4, and SULT2A1. These results will require replication in larger studies. [ABSTRACT FROM AUTHOR]
Published: 2012
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28. Antidiabetic Potential of Medicinal Plants and Their Active Components

Author: Bahare Salehi, Karina Ramírez-Alarcón, Nanjangud V. Anil Kumar, William N. Setzer, Patrick Valere Tsouh Fokou, Yasaman Taheri, Antoni Sureda, Seyed Abdulmajid Ayatollahi, William C. Cho, Farukh Sharopov, Zainul Amiruddin Zakaria, Elise Adrian Ostrander, Massimo Lucarini, Raffaele Capasso, Antonello Santini, Atta-ur-Rahman, Alessandra Durazzo, Muhammad Iqbal Choudhary, Athar Ata, Ana M. Ruiz-Ortega, Marcello Iriti, Javad Sharifi-Rad, Miquel Martorell, Farzad Kobarfard, Salehi, B, Ata, A, V Anil Kumar, N, Sharopov, F, Ramírez-Alarcón, K, Ruiz-Ortega, A, Abdulmajid Ayatollahi, S, Tsouh Fokou, Pv, Kobarfard, F, Amiruddin Zakaria, Z, Iriti, M, Taheri, Y, Martorell, M, Sureda, A, Setzer, Wn, Durazzo, A, Lucarini, M, Santini, A, Capasso, Raffaele, Ostrander, Ea, Atta-ur-Rahman, Choudhary, Mi, Cho, Wc, and Sharifi-Rad, J.
Subjects: Blood Glucose, Diabetes mellitu, glucosa sanguínea, humanos, lcsh:QR1-502, Active components, Review, regulación de la expresión génica, Biochemistry, antihyperglycemic, lcsh:Microbiology, ensayos clínicos como asunto, 03 medical and health sciences, Health problems, 0302 clinical medicine, Diabetes mellitus, medicinal plant, plantas, medicine, Animals, Humans, Hypoglycemic Agents, Gene Regulatory Networks, Medicinal plants, Molecular Biology, Antidiabetic agents, 030304 developmental biology, 0303 health sciences, Clinical Trials as Topic, Plants, Medicinal, Traditional medicine, Plant Extracts, antidiabetic, extractos de plantas, Plants, medicine.disease, hypoglycemic, Gene Expression Regulation, hipoglicemiantes, 030220 oncology & carcinogenesis, animales, redes génicas reguladoras, medicinal plants
Abstract: Diabetes mellitus is one of the major health problems in the world, the incidence and associated mortality are increasing. Inadequate regulation of the blood sugar imposes serious consequences for health. Conventional antidiabetic drugs are effective, however, also with unavoidable side effects. On the other hand, medicinal plants may act as an alternative source of antidiabetic agents. Examples of medicinal plants with antidiabetic potential are described, with focuses on preclinical and clinical studies. The beneficial potential of each plant matrix is given by the combined and concerted action of their profile of biologically active compounds., This work was supported by CONICYT PIA/APOYO CCTE AFB170007 and by the Institute of Health Carlos III (CIBEROBN CB12/03/30038).
Published: 2019

29. BRCA1 mutations in a population-based sample of young women with breast cancer.

Author: Langston AA, Malone KE, Thompson JD, Daling JR, and Ostrander EA
Published: 1996

30. Genomic analyses identify 15 susceptibility loci and reveal HDAC2 , SOX2-OT , and IGF2BP2 in a naturally-occurring canine model of gastric cancer.

Author: Cook SR, Hugen S, Hayward JJ, Famula TR, Belanger JM, McNiel E, Fieten H, Oberbauer AM, Leegwater PAJ, Ostrander EA, Mandigers PJJ, and Evans JM
Abstract: Gastric cancer (GC) is the fifth most common human cancer worldwide, but the genetic etiology is largely unknown. We performed a Bayesian genome-wide association study and selection analyses in a naturally-occurring canine model of GC, the Belgian Tervuren and Sheepdog breeds, to elucidate underlying genetic risk factors. We identified 15 loci with over 90% predictive accuracy for the GC phenotype. Variant filtering revealed germline putative regulatory variants for the EPAS1 ( HIF2A ) and PTEN genes and a coding variant in CD101 . Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois at SOX2-OT and IGF2BP2 . Among Tervuren and Sheepdogs, HDAC2 putative regulatory variants were present at comparatively high frequency and were associated with GC. Here, we describe a complex genetic architecture governing GC in a dog model, including genes such as PDZRN3 , that have not been associated with human GC., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.
Published: 2024
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31. Large-scale genomic analysis of the domestic dog informs biological discovery.

Author: Buckley RM and Ostrander EA
Subjects: Dogs genetics, Animals, Genetic Variation, Whole Genome Sequencing methods, Genomics methods, Genome
Abstract: Recent advances in genomics, coupled with a unique population structure and remarkable levels of variation, have propelled the domestic dog to new levels as a system for understanding fundamental principles in mammalian biology. Central to this advance are more than 350 recognized breeds, each a closed population that has undergone selection for unique features. Genetic variation in the domestic dog is particularly well characterized compared with other domestic mammals, with almost 3000 high-coverage genomes publicly available. Importantly, as the number of sequenced genomes increases, new avenues for analysis are becoming available. Herein, we discuss recent discoveries in canine genomics regarding behavior, morphology, and disease susceptibility. We explore the limitations of current data sets for variant interpretation, tradeoffs between sequencing strategies, and the burgeoning role of long-read genomes for capturing structural variants. In addition, we consider how large-scale collections of whole-genome sequence data drive rare variant discovery and assess the geographic distribution of canine diversity, which identifies Asia as a major source of missing variation. Finally, we review recent comparative genomic analyses that will facilitate annotation of the noncoding genome in dogs., (Published by Cold Spring Harbor Laboratory Press.)
Published: 2024
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32. Co-analysis of methylation platforms for signatures of biological aging in the domestic dog reveals previously unexplored confounding factors.

Author: Armero AS, Buckley RM, Mboning L, Spatola GJ, Horvath S, Pellegrini M, and Ostrander EA
Subjects: Animals, Dogs, Epigenesis, Genetic, DNA Methylation, Aging genetics, Longevity genetics
Abstract: Chronological age reveals the number of years an individual has lived since birth. By contrast, biological age varies between individuals of the same chronological age at a rate reflective of physiological decline. Differing rates of physiological decline are related to longevity and result from genetics, environment, behavior, and disease. The creation of methylation biological age predictors is a long-standing challenge in aging research due to the lack of individual pre-mortem longevity data. The consistent differences in longevity between domestic dog breeds enable the construction of biological age estimators which can, in turn, be contrasted with methylation measurements to elucidate mechanisms of biological aging. We draw on three flagship methylation studies using distinct measurement platforms and tissues to assess the feasibility of creating biological age methylation clocks in the dog. We expand epigenetic clock building strategies to accommodate phylogenetic relationships between individuals, thus controlling for the use of breed standard metrics. We observe that biological age methylation clocks are affected by population stratification and require heavy parameterization to achieve effective predictions. Finally, we observe that methylation-related markers reflecting biological age signals are rare and do not colocalize between datasets.
Published: 2024
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33. Dogs and their genes: what ever will they think of next?

Author: Ostrander EA
Subjects: Animals, Dogs genetics, Humans, History, 21st Century, History, 20th Century, Genetics history, Awards and Prizes
Abstract: The Edward Novitski Prize recognizes creativity and intellectual ingenuity in the solution of problems in genetics research. The prize honors scientific experimental work-either a single experimental accomplishment or a body of work. Ostrander is recognized for work developing the domestic dog as an experimental system for solving fundamental biological problems and identifying genetic sequences of relevance to human health and disease. Including work on disease and behavioral health, Ostrander has shown a dedication to creative methods for understanding canine genetics and the value of translating research organisms to human genetics., Competing Interests: Conflicts of interest The author(s) declare no conflicts of interest., (Published by Oxford University Press on behalf of The Genetics Society of America 2024.)
Published: 2024
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34. Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants.

Author: Foley GR, Marthick JR, Lucas SE, Raspin K, Banks A, Stanford JL, Ostrander EA, FitzGerald LM, and Dickinson JL
Abstract: Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (M QLS ) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10 -4 ) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.
Published: 2024
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35. Imputation of ancient canid genomes reveals inbreeding history over the past 10,000 years.

Author: Bougiouri K, Aninta SG, Charlton S, Harris A, Carmagnini A, Piličiauskienė G, Feuerborn TR, Scarsbrook L, Tabadda K, Blaževičius P, Parker HG, Gopalakrishnan S, Larson G, Ostrander EA, Irving-Pease EK, Frantz LAF, and Racimo F
Abstract: The multi-millenia long history between dogs and humans has placed them at the forefront of archeological and genomic research. Despite ongoing efforts including the analysis of ancient dog and wolf genomes, many questions remain regarding their geographic and temporal origins, and the microevolutionary processes that led to the diversity of breeds today. Although ancient genomes provide valuable information, their use is hindered by low depth of coverage and post-mortem damage, which inhibits confident genotype calling. In the present study, we assess how genotype imputation of ancient dog and wolf genomes, utilising a large reference panel, can improve the resolution provided by ancient datasets. Imputation accuracy was evaluated by down-sampling high coverage dog and wolf genomes to 0.05-2x coverage and comparing concordance between imputed and high coverage genotypes. We measured the impact of imputation on principal component analyses and runs of homozygosity. Our findings show high (R 2 >0.9) imputation accuracy for dogs with coverage as low as 0.5x and for wolves as low as 1.0x. We then imputed a dataset of 90 ancient dog and wolf genomes, to assess changes in inbreeding during the last 10,000 years of dog evolution. Ancient dog and wolf populations generally exhibited lower inbreeding levels than present-day individuals. Interestingly, regions with low ROH density maintained across ancient and present-day samples were significantly associated with genes related to olfaction and immune response. Our study indicates that imputing ancient canine genomes is a viable strategy that allows for the use of analytical methods previously limited to high-quality genetic data.
Published: 2024
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36. Multiple ancestries and shared gene flow among modern livestock guarding dogs.

Author: Coutinho-Lima D, Dreger DL, Doadrio I, Parker HG, Ghanavi HR, Frantz L, Larson G, Ostrander EA, and Godinho R
Abstract: Livestock guarding dogs (LGDs) have been used to protect livestock for millennia. While previous works suggested a single origin of modern LGDs, the degree and source of shared ancestry have not been tested. To address this, we generated genome-wide SNP data from 304 LGDs and combined it with public genomic data from 2,183 modern and 22 ancient dogs. Our findings reveal shared ancestry and extensive gene flow among modern LGD breeds which we attribute to historical livestock migrations. Additionally, admixture between LGDs and free-ranging dogs argues against reproductive isolation as a core mechanism for maintaining the specialized skills of LGDs. Finally, we identify two lineages within modern LGDs and uncover multiple ancestries tracing back to distinct Eurasian ancient dogs, concordant with the absence of a single ancestor. Overall, our work explores the complex evolutionary history of LGDs, offering valuable insights into how human and livestock co-migrations shaped this functional group., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)
Published: 2024
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37. Genome-wide analyses reveals an association between invasive urothelial carcinoma in the Shetland sheepdog and NIPAL1.

Author: Parker HG, Harris AC, Plassais J, Dhawan D, Kim EM, Knapp DW, and Ostrander EA
Abstract: Naturally occurring canine invasive urinary carcinoma (iUC) closely resembles human muscle invasive bladder cancer in terms of histopathology, metastases, response to therapy, and low survival rate. The heterogeneous nature of the disease has led to the association of large numbers of risk loci in humans, however most are of small effect. There exists a need for new and accurate animal models of invasive bladder cancer. In dogs, distinct breeds show markedly different rates of iUC, thus presenting an opportunity to identify additional risk factors and overcome the locus heterogeneity encountered in human mapping studies. In the association study presented here, inclusive of 100 Shetland sheepdogs and 58 dogs of other breeds, we identify a homozygous protein altering point mutation within the NIPAL1 gene which increases risk by eight-fold (OR = 8.42, CI = 3.12-22.71), accounting for nearly 30% of iUC risk in the Shetland sheepdog. Inclusion of six additional loci accounts for most of the disease risk in the breed and explains nearly 75% of the phenotypes in this study. When combined with sequence data from tumors, we show that variation in the MAPK signaling pathway is an overarching cause of iUC susceptibility in dogs., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Published: 2024
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38. Idiopathic Epilepsy Risk Allele Trends in Belgian Tervuren: A Longitudinal Genetic Analysis.

Author: Kinsey N, Belanger JM, Mandigers PJJ, Leegwater PA, Heinonen T, Hytönen MK, Lohi H, Ostrander EA, and Oberbauer AM
Subjects: Animals, Dogs, Alleles, Belgium epidemiology, Seizures, Gene Frequency, Epilepsy
Abstract: Idiopathic epilepsy (IE) has been known to be inherited in the Belgian Tervuren for many decades. Risk genotypes for IE in this breed have recently been identified on Canis familiaris chromosomes (CFA) 14 and 37. In the current study, the allele frequencies of these loci were analyzed to determine whether dog breeders had employed a purposeful selection against IE, leading to a reduction in risk-associated allele frequency within the breed over time. The allele frequencies of two generational groupings of Belgian Tervuren with and without IE were compared. Allele frequencies for risk-associated alleles on CFA14 were unchanged between 1985 and 2015, whereas those on CFA37 increased during that time in the control population ( p < 0.05). In contrast, dogs with IE showed a decrease ( p < 0.05) in the IE risk-associated allele frequency at the CFA37 locus. Seizure prevalence in the Belgian Tervuren appears to be increasing. These results suggest that, despite awareness that IE is inherited, selection against IE has not been successful.
Published: 2024
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39. The history of Coast Salish "woolly dogs" revealed by ancient genomics and Indigenous Knowledge.

Author: Lin AT, Hammond-Kaarremaa L, Liu HL, Stantis C, McKechnie I, Pavel M, Pavel SSM, Wyss SSÁ, Sparrow DQ, Carr K, Aninta SG, Perri A, Hartt J, Bergström A, Carmagnini A, Charlton S, Dalén L, Feuerborn TR, France CAM, Gopalakrishnan S, Grimes V, Harris A, Kavich G, Sacks BN, Sinding MS, Skoglund P, Stanton DWG, Ostrander EA, Larson G, Armstrong CG, Frantz LAF, Hawkins MTR, and Kistler L
Subjects: Animals, Genomics, Northwestern United States, Breeding, Dogs anatomy & histology, Dogs classification, Dogs genetics, Wool, Selection, Genetic
Abstract: Ancestral Coast Salish societies in the Pacific Northwest kept long-haired "woolly dogs" that were bred and cared for over millennia. However, the dog wool-weaving tradition declined during the 19th century, and the population was lost. In this study, we analyzed genomic and isotopic data from a preserved woolly dog pelt from "Mutton," collected in 1859. Mutton is the only known example of an Indigenous North American dog with dominant precolonial ancestry postdating the onset of settler colonialism. We identified candidate genetic variants potentially linked with their distinct woolly phenotype. We integrated these data with interviews from Coast Salish Elders, Knowledge Keepers, and weavers about shared traditional knowledge and memories surrounding woolly dogs, their importance within Coast Salish societies, and how colonial policies led directly to their disappearance.
Published: 2023
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40. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

Author: Wang A, Shen J, Rodriguez AA, Saunders EJ, Chen F, Janivara R, Darst BF, Sheng X, Xu Y, Chou AJ, Benlloch S, Dadaev T, Brook MN, Plym A, Sahimi A, Hoffman TJ, Takahashi A, Matsuda K, Momozawa Y, Fujita M, Laisk T, Figuerêdo J, Muir K, Ito S, Liu X, Uchio Y, Kubo M, Kamatani Y, Lophatananon A, Wan P, Andrews C, Lori A, Choudhury PP, Schleutker J, Tammela TLJ, Sipeky C, Auvinen A, Giles GG, Southey MC, MacInnis RJ, Cybulski C, Wokolorczyk D, Lubinski J, Rentsch CT, Cho K, Mcmahon BH, Neal DE, Donovan JL, Hamdy FC, Martin RM, Nordestgaard BG, Nielsen SF, Weischer M, Bojesen SE, Røder A, Stroomberg HV, Batra J, Chambers S, Horvath L, Clements JA, Tilly W, Risbridger GP, Gronberg H, Aly M, Szulkin R, Eklund M, Nordstrom T, Pashayan N, Dunning AM, Ghoussaini M, Travis RC, Key TJ, Riboli E, Park JY, Sellers TA, Lin HY, Albanes D, Weinstein S, Cook MB, Mucci LA, Giovannucci E, Lindstrom S, Kraft P, Hunter DJ, Penney KL, Turman C, Tangen CM, Goodman PJ, Thompson IM Jr, Hamilton RJ, Fleshner NE, Finelli A, Parent MÉ, Stanford JL, Ostrander EA, Koutros S, Beane Freeman LE, Stampfer M, Wolk A, Håkansson N, Andriole GL, Hoover RN, Machiela MJ, Sørensen KD, Borre M, Blot WJ, Zheng W, Yeboah ED, Mensah JE, Lu YJ, Zhang HW, Feng N, Mao X, Wu Y, Zhao SC, Sun Z, Thibodeau SN, McDonnell SK, Schaid DJ, West CML, Barnett G, Maier C, Schnoeller T, Luedeke M, Kibel AS, Drake BF, Cussenot O, Cancel-Tassin G, Menegaux F, Truong T, Koudou YA, John EM, Grindedal EM, Maehle L, Khaw KT, Ingles SA, Stern MC, Vega A, Gómez-Caamaño A, Fachal L, Rosenstein BS, Kerns SL, Ostrer H, Teixeira MR, Paulo P, Brandão A, Watya S, Lubwama A, Bensen JT, Butler EN, Mohler JL, Taylor JA, Kogevinas M, Dierssen-Sotos T, Castaño-Vinyals G, Cannon-Albright L, Teerlink CC, Huff CD, Pilie P, Yu Y, Bohlender RJ, Gu J, Strom SS, Multigner L, Blanchet P, Brureau L, Kaneva R, Slavov C, Mitev V, Leach RJ, Brenner H, Chen X, Holleczek B, Schöttker B, Klein EA, Hsing AW, Kittles RA, Murphy AB, Logothetis CJ, Kim J, Neuhausen SL, Steele L, Ding YC, Isaacs WB, Nemesure B, Hennis AJM, Carpten J, Pandha H, Michael A, De Ruyck K, De Meerleer G, Ost P, Xu J, Razack A, Lim J, Teo SH, Newcomb LF, Lin DW, Fowke JH, Neslund-Dudas CM, Rybicki BA, Gamulin M, Lessel D, Kulis T, Usmani N, Abraham A, Singhal S, Parliament M, Claessens F, Joniau S, Van den Broeck T, Gago-Dominguez M, Castelao JE, Martinez ME, Larkin S, Townsend PA, Aukim-Hastie C, Bush WS, Aldrich MC, Crawford DC, Srivastava S, Cullen J, Petrovics G, Casey G, Wang Y, Tettey Y, Lachance J, Tang W, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Yamoah K, Govindasami K, Chokkalingam AP, Keaton JM, Hellwege JN, Clark PE, Jalloh M, Gueye SM, Niang L, Ogunbiyi O, Shittu O, Amodu O, Adebiyi AO, Aisuodionoe-Shadrach OI, Ajibola HO, Jamda MA, Oluwole OP, Nwegbu M, Adusei B, Mante S, Darkwa-Abrahams A, Diop H, Gundell SM, Roobol MJ, Jenster G, van Schaik RHN, Hu JJ, Sanderson M, Kachuri L, Varma R, McKean-Cowdin R, Torres M, Preuss MH, Loos RJF, Zawistowski M, Zöllner S, Lu Z, Van Den Eeden SK, Easton DF, Ambs S, Edwards TL, Mägi R, Rebbeck TR, Fritsche L, Chanock SJ, Berndt SI, Wiklund F, Nakagawa H, Witte JS, Gaziano JM, Justice AC, Mancuso N, Terao C, Eeles RA, Kote-Jarai Z, Madduri RK, Conti DV, and Haiman CA
Subjects: Humans, Male, Black People genetics, Genome-Wide Association Study, Hispanic or Latino genetics, Polymorphism, Single Nucleotide, Risk Factors, White People genetics, Asian People genetics, Genetic Predisposition to Disease, Prostatic Neoplasms genetics
Abstract: The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Published: 2023
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41. Author Correction: Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture.

Author: Meadows JRS, Kidd JM, Wang GD, Parker HG, Schall PZ, Bianchi M, Christmas MJ, Bougiouri K, Buckley RM, Hitte C, Nguyen AK, Wang C, Jagannathan V, Niskanen JE, Frantz LAF, Arumilli M, Hundi S, Lindblad-Toh K, Ginja C, Agustina KK, André C, Boyko AR, Davis BW, Drögemüller M, Feng XY, Gkagkavouzis K, Iliopoulos G, Harris AC, Hytönen MK, Kalthof DC, Liu YH, Lymberakis P, Poulakakis N, Pires AE, Racimo F, Ramos-Almodovar F, Savolainen P, Venetsani S, Tammen I, Triantafyllidis A, vonHoldt B, Wayne RK, Larson G, Nicholas FW, Lohi H, Leeb T, Zhang YP, and Ostrander EA
Published: 2023
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42. Centuries of genome instability and evolution in soft-shell clam, Mya arenaria, bivalve transmissible neoplasia.

Author: Hart SFM, Yonemitsu MA, Giersch RM, Garrett FES, Beal BF, Arriagada G, Davis BW, Ostrander EA, Goff SP, and Metzger MJ
Subjects: Animals, Genomic Instability genetics, Mya genetics, Neoplasms
Abstract: Transmissible cancers are infectious parasitic clones that metastasize to new hosts, living past the death of the founder animal in which the cancer initiated. We investigated the evolutionary history of a cancer lineage that has spread though the soft-shell clam (Mya arenaria) population by assembling a chromosome-scale soft-shell clam reference genome and characterizing somatic mutations in transmissible cancer. We observe high mutation density, widespread copy-number gain, structural rearrangement, loss of heterozygosity, variable telomere lengths, mitochondrial genome expansion and transposable element activity, all indicative of an unstable cancer genome. We also discover a previously unreported mutational signature associated with overexpression of an error-prone polymerase and use this to estimate the lineage to be >200 years old. Our study reveals the ability for an invertebrate cancer lineage to survive for centuries while its genome continues to structurally mutate, likely contributing to the evolution of this lineage as a parasitic cancer., (© 2023. The Author(s).)
Published: 2023
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43. Author Correction: Universal DNA methylation age across mammalian tissues.

Author: Lu AT, Fei Z, Haghani A, Robeck TR, Zoller JA, Li CZ, Lowe R, Yan Q, Zhang J, Vu H, Ablaeva J, Acosta-Rodriguez VA, Adams DM, Almunia J, Aloysius A, Ardehali R, Arneson A, Baker CS, Banks G, Belov K, Bennett NC, Black P, Blumstein DT, Bors EK, Breeze CE, Brooke RT, Brown JL, Carter GG, Caulton A, Cavin JM, Chakrabarti L, Chatzistamou I, Chen H, Cheng K, Chiavellini P, Choi OW, Clarke SM, Cooper LN, Cossette ML, Day J, DeYoung J, DiRocco S, Dold C, Ehmke EE, Emmons CK, Emmrich S, Erbay E, Erlacher-Reid C, Faulkes CG, Ferguson SH, Finno CJ, Flower JE, Gaillard JM, Garde E, Gerber L, Gladyshev VN, Gorbunova V, Goya RG, Grant MJ, Green CB, Hales EN, Hanson MB, Hart DW, Haulena M, Herrick K, Hogan AN, Hogg CJ, Hore TA, Huang T, Izpisua Belmonte JC, Jasinska AJ, Jones G, Jourdain E, Kashpur O, Katcher H, Katsumata E, Kaza V, Kiaris H, Kobor MS, Kordowitzki P, Koski WR, Krützen M, Kwon SB, Larison B, Lee SG, Lehmann M, Lemaitre JF, Levine AJ, Li C, Li X, Lim AR, Lin DTS, Lindemann DM, Little TJ, Macoretta N, Maddox D, Matkin CO, Mattison JA, McClure M, Mergl J, Meudt JJ, Montano GA, Mozhui K, Munshi-South J, Naderi A, Nagy M, Narayan P, Nathanielsz PW, Nguyen NB, Niehrs C, O'Brien JK, O'Tierney Ginn P, Odom DT, Ophir AG, Osborn S, Ostrander EA, Parsons KM, Paul KC, Pellegrini M, Peters KJ, Pedersen AB, Petersen JL, Pietersen DW, Pinho GM, Plassais J, Poganik JR, Prado NA, Reddy P, Rey B, Ritz BR, Robbins J, Rodriguez M, Russell J, Rydkina E, Sailer LL, Salmon AB, Sanghavi A, Schachtschneider KM, Schmitt D, Schmitt T, Schomacher L, Schook LB, Sears KE, Seifert AW, Seluanov A, Shafer ABA, Shanmuganayagam D, Shindyapina AV, Simmons M, Singh K, Sinha I, Slone J, Snell RG, Soltanmaohammadi E, Spangler ML, Spriggs MC, Staggs L, Stedman N, Steinman KJ, Stewart DT, Sugrue VJ, Szladovits B, Takahashi JS, Takasugi M, Teeling EC, Thompson MJ, Van Bonn B, Vernes SC, Villar D, Vinters HV, Wallingford MC, Wang N, Wayne RK, Wilkinson GS, Williams CK, Williams RW, Yang XW, Yao M, Young BG, Zhang B, Zhang Z, Zhao P, Zhao Y, Zhou W, Zimmermann J, Ernst J, Raj K, and Horvath S
Published: 2023
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44. Universal DNA methylation age across mammalian tissues.

Author: Lu AT, Fei Z, Haghani A, Robeck TR, Zoller JA, Li CZ, Lowe R, Yan Q, Zhang J, Vu H, Ablaeva J, Acosta-Rodriguez VA, Adams DM, Almunia J, Aloysius A, Ardehali R, Arneson A, Baker CS, Banks G, Belov K, Bennett NC, Black P, Blumstein DT, Bors EK, Breeze CE, Brooke RT, Brown JL, Carter GG, Caulton A, Cavin JM, Chakrabarti L, Chatzistamou I, Chen H, Cheng K, Chiavellini P, Choi OW, Clarke SM, Cooper LN, Cossette ML, Day J, DeYoung J, DiRocco S, Dold C, Ehmke EE, Emmons CK, Emmrich S, Erbay E, Erlacher-Reid C, Faulkes CG, Ferguson SH, Finno CJ, Flower JE, Gaillard JM, Garde E, Gerber L, Gladyshev VN, Gorbunova V, Goya RG, Grant MJ, Green CB, Hales EN, Hanson MB, Hart DW, Haulena M, Herrick K, Hogan AN, Hogg CJ, Hore TA, Huang T, Izpisua Belmonte JC, Jasinska AJ, Jones G, Jourdain E, Kashpur O, Katcher H, Katsumata E, Kaza V, Kiaris H, Kobor MS, Kordowitzki P, Koski WR, Krützen M, Kwon SB, Larison B, Lee SG, Lehmann M, Lemaitre JF, Levine AJ, Li C, Li X, Lim AR, Lin DTS, Lindemann DM, Little TJ, Macoretta N, Maddox D, Matkin CO, Mattison JA, McClure M, Mergl J, Meudt JJ, Montano GA, Mozhui K, Munshi-South J, Naderi A, Nagy M, Narayan P, Nathanielsz PW, Nguyen NB, Niehrs C, O'Brien JK, O'Tierney Ginn P, Odom DT, Ophir AG, Osborn S, Ostrander EA, Parsons KM, Paul KC, Pellegrini M, Peters KJ, Pedersen AB, Petersen JL, Pietersen DW, Pinho GM, Plassais J, Poganik JR, Prado NA, Reddy P, Rey B, Ritz BR, Robbins J, Rodriguez M, Russell J, Rydkina E, Sailer LL, Salmon AB, Sanghavi A, Schachtschneider KM, Schmitt D, Schmitt T, Schomacher L, Schook LB, Sears KE, Seifert AW, Seluanov A, Shafer ABA, Shanmuganayagam D, Shindyapina AV, Simmons M, Singh K, Sinha I, Slone J, Snell RG, Soltanmaohammadi E, Spangler ML, Spriggs MC, Staggs L, Stedman N, Steinman KJ, Stewart DT, Sugrue VJ, Szladovits B, Takahashi JS, Takasugi M, Teeling EC, Thompson MJ, Van Bonn B, Vernes SC, Villar D, Vinters HV, Wallingford MC, Wang N, Wayne RK, Wilkinson GS, Williams CK, Williams RW, Yang XW, Yao M, Young BG, Zhang B, Zhang Z, Zhao P, Zhao Y, Zhou W, Zimmermann J, Ernst J, Raj K, and Horvath S
Subjects: Humans, Mice, Animals, Aging genetics, Longevity genetics, Mammals genetics, DNA Methylation genetics, Epigenesis, Genetic
Abstract: Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals., (© 2023. The Author(s).)
Published: 2023
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45. Genome sequencing of 2000 canids by the Dog10K consortium advances the understanding of demography, genome function and architecture.

Author: Meadows JRS, Kidd JM, Wang GD, Parker HG, Schall PZ, Bianchi M, Christmas MJ, Bougiouri K, Buckley RM, Hitte C, Nguyen AK, Wang C, Jagannathan V, Niskanen JE, Frantz LAF, Arumilli M, Hundi S, Lindblad-Toh K, Ginja C, Agustina KK, André C, Boyko AR, Davis BW, Drögemüller M, Feng XY, Gkagkavouzis K, Iliopoulos G, Harris AC, Hytönen MK, Kalthoff DC, Liu YH, Lymberakis P, Poulakakis N, Pires AE, Racimo F, Ramos-Almodovar F, Savolainen P, Venetsani S, Tammen I, Triantafyllidis A, vonHoldt B, Wayne RK, Larson G, Nicholas FW, Lohi H, Leeb T, Zhang YP, and Ostrander EA
Subjects: Dogs, Animals, Chromosome Mapping, Alleles, Polymorphism, Single Nucleotide, Nucleotides, Demography, Wolves genetics
Abstract: Background: The international Dog10K project aims to sequence and analyze several thousand canine genomes. Incorporating 20 × data from 1987 individuals, including 1611 dogs (321 breeds), 309 village dogs, 63 wolves, and four coyotes, we identify genomic variation across the canid family, setting the stage for detailed studies of domestication, behavior, morphology, disease susceptibility, and genome architecture and function., Results: We report the analysis of > 48 M single-nucleotide, indel, and structural variants spanning the autosomes, X chromosome, and mitochondria. We discover more than 75% of variation for 239 sampled breeds. Allele sharing analysis indicates that 94.9% of breeds form monophyletic clusters and 25 major clades. German Shepherd Dogs and related breeds show the highest allele sharing with independent breeds from multiple clades. On average, each breed dog differs from the UU_Cfam_GSD_1.0 reference at 26,960 deletions and 14,034 insertions greater than 50 bp, with wolves having 14% more variants. Discovered variants include retrogene insertions from 926 parent genes. To aid functional prioritization, single-nucleotide variants were annotated with SnpEff and Zoonomia phyloP constraint scores. Constrained positions were negatively correlated with allele frequency. Finally, the utility of the Dog10K data as an imputation reference panel is assessed, generating high-confidence calls across varied genotyping platform densities including for breeds not included in the Dog10K collection., Conclusions: We have developed a dense dataset of 1987 sequenced canids that reveals patterns of allele sharing, identifies likely functional variants, informs breed structure, and enables accurate imputation. Dog10K data are publicly available., (© 2023. BioMed Central Ltd., part of Springer Nature.)
Published: 2023
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46. DNA methylation networks underlying mammalian traits.

Author: Haghani A, Li CZ, Robeck TR, Zhang J, Lu AT, Ablaeva J, Acosta-Rodríguez VA, Adams DM, Alagaili AN, Almunia J, Aloysius A, Amor NMS, Ardehali R, Arneson A, Baker CS, Banks G, Belov K, Bennett NC, Black P, Blumstein DT, Bors EK, Breeze CE, Brooke RT, Brown JL, Carter G, Caulton A, Cavin JM, Chakrabarti L, Chatzistamou I, Chavez AS, Chen H, Cheng K, Chiavellini P, Choi OW, Clarke S, Cook JA, Cooper LN, Cossette ML, Day J, DeYoung J, Dirocco S, Dold C, Dunnum JL, Ehmke EE, Emmons CK, Emmrich S, Erbay E, Erlacher-Reid C, Faulkes CG, Fei Z, Ferguson SH, Finno CJ, Flower JE, Gaillard JM, Garde E, Gerber L, Gladyshev VN, Goya RG, Grant MJ, Green CB, Hanson MB, Hart DW, Haulena M, Herrick K, Hogan AN, Hogg CJ, Hore TA, Huang T, Izpisua Belmonte JC, Jasinska AJ, Jones G, Jourdain E, Kashpur O, Katcher H, Katsumata E, Kaza V, Kiaris H, Kobor MS, Kordowitzki P, Koski WR, Krützen M, Kwon SB, Larison B, Lee SG, Lehmann M, Lemaître JF, Levine AJ, Li X, Li C, Lim AR, Lin DTS, Lindemann DM, Liphardt SW, Little TJ, Macoretta N, Maddox D, Matkin CO, Mattison JA, McClure M, Mergl J, Meudt JJ, Montano GA, Mozhui K, Munshi-South J, Murphy WJ, Naderi A, Nagy M, Narayan P, Nathanielsz PW, Nguyen NB, Niehrs C, Nyamsuren B, O'Brien JK, Ginn PO, Odom DT, Ophir AG, Osborn S, Ostrander EA, Parsons KM, Paul KC, Pedersen AB, Pellegrini M, Peters KJ, Petersen JL, Pietersen DW, Pinho GM, Plassais J, Poganik JR, Prado NA, Reddy P, Rey B, Ritz BR, Robbins J, Rodriguez M, Russell J, Rydkina E, Sailer LL, Salmon AB, Sanghavi A, Schachtschneider KM, Schmitt D, Schmitt T, Schomacher L, Schook LB, Sears KE, Seifert AW, Shafer ABA, Shindyapina AV, Simmons M, Singh K, Sinha I, Slone J, Snell RG, Soltanmohammadi E, Spangler ML, Spriggs M, Staggs L, Stedman N, Steinman KJ, Stewart DT, Sugrue VJ, Szladovits B, Takahashi JS, Takasugi M, Teeling EC, Thompson MJ, Van Bonn B, Vernes SC, Villar D, Vinters HV, Vu H, Wallingford MC, Wang N, Wilkinson GS, Williams RW, Yan Q, Yao M, Young BG, Zhang B, Zhang Z, Zhao Y, Zhao P, Zhou W, Zoller JA, Ernst J, Seluanov A, Gorbunova V, Yang XW, Raj K, and Horvath S
Subjects: Adult, Animals, Humans, Epigenome, Genome, Phylogeny, DNA Methylation, Epigenesis, Genetic, Mammals genetics
Abstract: Using DNA methylation profiles ( n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.
Published: 2023
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47. Genome-wide variant analyses reveal new patterns of admixture and population structure in Australian dingoes.

Author: Cairns KM, Crowther MS, Parker HG, Ostrander EA, and Letnic M
Subjects: Animals, Animals, Wild genetics, Australia, Genetic Markers, Genome genetics, Genotype, Dogs
Abstract: Admixture between species is a cause for concern in wildlife management. Canids are particularly vulnerable to interspecific hybridisation, and genetic admixture has shaped their evolutionary history. Microsatellite DNA testing, relying on a small number of genetic markers and geographically restricted reference populations, has identified extensive domestic dog admixture in Australian dingoes and driven conservation management policy. But there exists a concern that geographic variation in dingo genotypes could confound ancestry analyses that use a small number of genetic markers. Here, we apply genome-wide single-nucleotide polymorphism (SNP) genotyping to a set of 402 wild and captive dingoes collected from across Australia and then carry out comparisons to domestic dogs. We then perform ancestry modelling and biogeographic analyses to characterise population structure in dingoes and investigate the extent of admixture between dingoes and dogs in different regions of the continent. We show that there are at least five distinct dingo populations across Australia. We observed limited evidence of dog admixture in wild dingoes. Our work challenges previous reports regarding the occurrence and extent of dog admixture in dingoes, as our ancestry analyses show that previous assessments severely overestimate the degree of domestic dog admixture in dingo populations, particularly in south-eastern Australia. These findings strongly support the use of genome-wide SNP genotyping as a refined method for wildlife managers and policymakers to assess and inform dingo management policy and legislation moving forwards., (© 2023 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)
Published: 2023
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48. Remembering distinguished professor Robert K. Wayne.

Author: Leonard JA, von Holdt B, Smith TB, Sork VL, Shapiro B, Ostrander EA, Rieseberg LH, Van Valkenburgh B, and Lohmueller KE
Published: 2023
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49. Genomic Diversity and Runs of Homozygosity in Bernese Mountain Dogs.

Author: Letko A, Hédan B, Snell A, Harris AC, Jagannathan V, Andersson G, Holst BS, Ostrander EA, Quignon P, André C, and Leeb T
Subjects: Dogs, Animals, Cattle, Homozygote, Genotype, Genomics methods, Polymorphism, Single Nucleotide, Genome genetics
Abstract: Bernese mountain dogs are a large dog breed formed in the early 1900s in Switzerland. While originally farm dogs that were used for pulling carts, guarding, and driving cattle, today they are considered multi-purpose companion and family dogs. The breed is predisposed to several complex diseases, such as histiocytic sarcoma, degenerative myelopathy, or hip dysplasia. Using whole-genome sequencing (WGS) data, we assessed the genomic architecture of 33 unrelated dogs from four countries: France, Sweden, Switzerland, and the United States. Analysis of runs of homozygosity (ROH) identified 12,643 ROH with an average length of 2.29 Mb and an average inbreeding coefficient of 0.395. Multidimensional scaling analysis of the genetic relatedness revealed limited clustering of European versus USA dogs, suggesting exchanges of breeding stock between continents. Furthermore, only two mtDNA haplotypes were detected in the 33 studied dogs, both of which are widespread throughout multiple dog breeds. WGS-based ROH analyses revealed several fixed or nearly fixed regions harboring discreet morphological trait-associated as well as disease-associated genetic variants. Several genes involved in the regulation of immune cells were found in the ROH shared by all dogs, which is notable in the context of the breed's strong predisposition to hematopoietic cancers. High levels of inbreeding and relatedness, strongly exaggerated in the last 30 years, have likely led to the high prevalence of specific genetic disorders in this breed.
Published: 2023
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50. The dogs of Chernobyl: Demographic insights into populations inhabiting the nuclear exclusion zone.

Author: Spatola GJ, Buckley RM, Dillon M, Dutrow EV, Betz JA, Pilot M, Parker HG, Bogdanowicz W, Thomas R, Chyzhevskyi I, Milinevsky G, Kleiman N, Breen M, Ostrander EA, and Mousseau TA
Subjects: Dogs, Animals, Environment, Environmental Pollution, Demography, Chernobyl Nuclear Accident, Disasters
Abstract: The 1986 Chernobyl nuclear disaster initiated a series of catastrophic events resulting in long-term and widespread environmental contamination. We characterize the genetic structure of 302 dogs representing three free-roaming dog populations living within the power plant itself, as well as those 15 to 45 kilometers from the disaster site. Genome-wide profiles from Chernobyl, purebred and free-breeding dogs, worldwide reveal that the individuals from the power plant and Chernobyl City are genetically distinct, with the former displaying increased intrapopulation genetic similarity and differentiation. Analysis of shared ancestral genome segments highlights differences in the extent and timing of western breed introgression. Kinship analysis reveals 15 families, with the largest spanning all collection sites within the radioactive exclusion zone, reflecting migration of dogs between the power plant and Chernobyl City. This study presents the first characterization of a domestic species in Chernobyl, establishing their importance for genetic studies into the effects of exposure to long-term, low-dose ionizing radiation.
Published: 2023
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