Characterization of large structural genetic mosaicism in human autosomes

Mitchell J. Machiela, Weiyin Zhou, Joshua N. Sampson, Michael C. Dean, Kevin B. Jacobs, Amanda Black, Louise A. Brinton, I. Shou Chang, Chu Chen, Constance Chen, Kexin Chen, Linda S. Cook, Marta Crous Bou, Immaculata De Vivo, Jennifer Doherty, Christine M. Friedenreich, Mia M. Gaudet, Christopher A. Haiman, Susan E. Hankinson, Patricia Hartge & 179 others Brian E. Henderson, Yun Chul Hong, H. Dean Hosgood, Chao A. Hsiung, Wei Hu, David J. Hunter, Lea Jessop, Hee Nam Kim, Yeul Hong Kim, Young Tae Kim, Robert Klein, Peter Kraft, Qing Lan, Dongxin Lin, Jianjun Liu, Loic Le Marchand, Xiaolin Liang, Jolanta Lissowska, Lingeng Lu, Anthony M. Magliocco, Keitaro Matsuo, Sara H. Olson, Irene Orlow, Jae Yong Park, Loreall Pooler, Jennifer Prescott, Radhai Rastogi, Harvey A. Risch, Fredrick Schumacher, Adeline Seow, Veronica Wendy Setiawan, Hongbing Shen, Xin Sheng, Min Ho Shin, Xiao Ou Shu, David Vanden Berg, Jiu Cun Wang, Nicolas Wentzensen, Maria Pik Wong, Chen Wu, Tangchun Wu, Yi Long Wu, Lucy Xia, Hannah P. Yang, Pan Chyr Yang, Wei Zheng, Baosen Zhou, Christian C. Abnet, Demetrius Albanes, Melinda C. Aldrich, Christopher Amos, Laufey T. Amundadottir, Sonja I. Berndt, William J. Blot, Cathryn H. Bock, Paige M. Bracci, Laurie Burdett, Julie E. Buring, Mary A. Butler, Tania Carreón, Nilanjan Chatterjee, Charles C. Chung, Michael B. Cook, Michael Cullen, Faith G. Davis, Ti Ding, Eric J. Duell, Caroline G. Epstein, Jin Hu Fan, Jonine D. Figueroa, Joseph F. Fraumeni, Neal D. Freedman, Charles S. Fuchs, Yu Tang Gao, Susan M. Gapstur, Ana Patiño-Garcia, Montserrat Garcia-Closas, J. Michael Gaziano, Graham G. Giles, Elizabeth M. Gillanders, Edward L. Giovannucci, Lynn Goldin, Alisa M. Goldstein, Mark H. Greene, Goran Hallmans, Curtis C. Harris, Roger Henriksson, Elizabeth A. Holly, Robert N. Hoover, Nan Hu, Amy Hutchinson, Mazda Jenab, Christoffer Johansen, Kay Tee Khaw, Woon Puay Koh, Laurence N. Kolonel, Charles Kooperberg, Vittorio Krogh, Robert C. Kurtz, Andrea Lacroix, Annelie Landgren, Maria Teresa Landi, Donghui Li, Linda M. Liao, Nuria Malats, Katherine A. McGlynn, Lorna H. McNeill, Robert R. McWilliams, Beatrice S. Melin, Lisa Mirabello, Beata Peplonska, Ulrike Peters, Gloria M. Petersen, Ludmila Prokunina-Olsson, Mark Purdue, You Lin Qiao, Kari G. Rabe, Preetha Rajaraman, Francisco X. Real, Elio Riboli, Benjamín Rodríguez-Santiago, Nathaniel Rothman, Avima M. Ruder, Sharon A. Savage, Ann G. Schwartz, Kendra L. Schwartz, Howard D. Sesso, Gianluca Severi, Debra T. Silverman, Margaret R. Spitz, Victoria L. Stevens, Rachael Stolzenberg-Solomon, Daniel Stram, Ze Zhong Tang, Philip R. Taylor, Lauren R. Teras, Geoffrey S. Tobias, Kala Viswanathan, Sholom Wacholder, Zhaoming Wang, Stephanie J. Weinstein, William Wheeler, Emily White, John K. Wiencke, Brian M. Wolpin, Xifeng Wu, Jay S. Wunder, Kai Yu, Krista A. Zanetti, Anne Zeleniuch-Jacquotte, Regina G. Ziegler, Mariza De Andrade, Kathleen C. Barnes, Terri L Beaty, Laura J. Bierut, Karl C. Desch, Kimberly Doheny, Bjarke Feenstra, David Ginsburg, John A. Heit, Jae H. Kang, Cecilia A. Laurie, Jun Z. Li, William L. Lowe, Mary L. Marazita, Mads Melbye, Daniel B. Mirel, Jeffrey C. Murray, Sarah C. Nelson, Louis R. Pasquale, Kenneth Rice, Janey L. Wiggs, Anastasia Wise, Margaret Tucker, Luis A. Pérez-Jurado, Cathy C. Laurie, Neil E. Caporaso, Meredith Yeager, Stephen J. Chanock

Research output: Contribution to journalArticle

Abstract

Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10-31) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

Original languageEnglish (US)
Pages (from-to)487-497
Number of pages11
JournalAmerican Journal of Human Genetics
Volume96
Issue number3
DOIs
StatePublished - Mar 5 2015

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Mosaicism
Genome-Wide Association Study
Meta-Analysis
Genome
Population
Genes
Datasets

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Machiela, M. J., Zhou, W., Sampson, J. N., Dean, M. C., Jacobs, K. B., Black, A., ... Chanock, S. J. (2015). Characterization of large structural genetic mosaicism in human autosomes. American Journal of Human Genetics, 96(3), 487-497. https://doi.org/10.1016/j.ajhg.2015.01.011

Characterization of large structural genetic mosaicism in human autosomes. / Machiela, Mitchell J.; Zhou, Weiyin; Sampson, Joshua N.; Dean, Michael C.; Jacobs, Kevin B.; Black, Amanda; Brinton, Louise A.; Chang, I. Shou; Chen, Chu; Chen, Constance; Chen, Kexin; Cook, Linda S.; Crous Bou, Marta; De Vivo, Immaculata; Doherty, Jennifer; Friedenreich, Christine M.; Gaudet, Mia M.; Haiman, Christopher A.; Hankinson, Susan E.; Hartge, Patricia; Henderson, Brian E.; Hong, Yun Chul; Hosgood, H. Dean; Hsiung, Chao A.; Hu, Wei; Hunter, David J.; Jessop, Lea; Kim, Hee Nam; Kim, Yeul Hong; Kim, Young Tae; Klein, Robert; Kraft, Peter; Lan, Qing; Lin, Dongxin; Liu, Jianjun; Le Marchand, Loic; Liang, Xiaolin; Lissowska, Jolanta; Lu, Lingeng; Magliocco, Anthony M.; Matsuo, Keitaro; Olson, Sara H.; Orlow, Irene; Park, Jae Yong; Pooler, Loreall; Prescott, Jennifer; Rastogi, Radhai; Risch, Harvey A.; Schumacher, Fredrick; Seow, Adeline; Setiawan, Veronica Wendy; Shen, Hongbing; Sheng, Xin; Shin, Min Ho; Shu, Xiao Ou; Vanden Berg, David; Wang, Jiu Cun; Wentzensen, Nicolas; Wong, Maria Pik; Wu, Chen; Wu, Tangchun; Wu, Yi Long; Xia, Lucy; Yang, Hannah P.; Yang, Pan Chyr; Zheng, Wei; Zhou, Baosen; Abnet, Christian C.; Albanes, Demetrius; Aldrich, Melinda C.; Amos, Christopher; Amundadottir, Laufey T.; Berndt, Sonja I.; Blot, William J.; Bock, Cathryn H.; Bracci, Paige M.; Burdett, Laurie; Buring, Julie E.; Butler, Mary A.; Carreón, Tania; Chatterjee, Nilanjan; Chung, Charles C.; Cook, Michael B.; Cullen, Michael; Davis, Faith G.; Ding, Ti; Duell, Eric J.; Epstein, Caroline G.; Fan, Jin Hu; Figueroa, Jonine D.; Fraumeni, Joseph F.; Freedman, Neal D.; Fuchs, Charles S.; Gao, Yu Tang; Gapstur, Susan M.; Patiño-Garcia, Ana; Garcia-Closas, Montserrat; Gaziano, J. Michael; Giles, Graham G.; Gillanders, Elizabeth M.; Giovannucci, Edward L.; Goldin, Lynn; Goldstein, Alisa M.; Greene, Mark H.; Hallmans, Goran; Harris, Curtis C.; Henriksson, Roger; Holly, Elizabeth A.; Hoover, Robert N.; Hu, Nan; Hutchinson, Amy; Jenab, Mazda; Johansen, Christoffer; Khaw, Kay Tee; Koh, Woon Puay; Kolonel, Laurence N.; Kooperberg, Charles; Krogh, Vittorio; Kurtz, Robert C.; Lacroix, Andrea; Landgren, Annelie; Landi, Maria Teresa; Li, Donghui; Liao, Linda M.; Malats, Nuria; McGlynn, Katherine A.; McNeill, Lorna H.; McWilliams, Robert R.; Melin, Beatrice S.; Mirabello, Lisa; Peplonska, Beata; Peters, Ulrike; Petersen, Gloria M.; Prokunina-Olsson, Ludmila; Purdue, Mark; Qiao, You Lin; Rabe, Kari G.; Rajaraman, Preetha; Real, Francisco X.; Riboli, Elio; Rodríguez-Santiago, Benjamín; Rothman, Nathaniel; Ruder, Avima M.; Savage, Sharon A.; Schwartz, Ann G.; Schwartz, Kendra L.; Sesso, Howard D.; Severi, Gianluca; Silverman, Debra T.; Spitz, Margaret R.; Stevens, Victoria L.; Stolzenberg-Solomon, Rachael; Stram, Daniel; Tang, Ze Zhong; Taylor, Philip R.; Teras, Lauren R.; Tobias, Geoffrey S.; Viswanathan, Kala; Wacholder, Sholom; Wang, Zhaoming; Weinstein, Stephanie J.; Wheeler, William; White, Emily; Wiencke, John K.; Wolpin, Brian M.; Wu, Xifeng; Wunder, Jay S.; Yu, Kai; Zanetti, Krista A.; Zeleniuch-Jacquotte, Anne; Ziegler, Regina G.; De Andrade, Mariza; Barnes, Kathleen C.; Beaty, Terri L; Bierut, Laura J.; Desch, Karl C.; Doheny, Kimberly; Feenstra, Bjarke; Ginsburg, David; Heit, John A.; Kang, Jae H.; Laurie, Cecilia A.; Li, Jun Z.; Lowe, William L.; Marazita, Mary L.; Melbye, Mads; Mirel, Daniel B.; Murray, Jeffrey C.; Nelson, Sarah C.; Pasquale, Louis R.; Rice, Kenneth; Wiggs, Janey L.; Wise, Anastasia; Tucker, Margaret; Pérez-Jurado, Luis A.; Laurie, Cathy C.; Caporaso, Neil E.; Yeager, Meredith; Chanock, Stephen J.

In: American Journal of Human Genetics, Vol. 96, No. 3, 05.03.2015, p. 487-497.

Research output: Contribution to journalArticle

Machiela, MJ, Zhou, W, Sampson, JN, Dean, MC, Jacobs, KB, Black, A, Brinton, LA, Chang, IS, Chen, C, Chen, C, Chen, K, Cook, LS, Crous Bou, M, De Vivo, I, Doherty, J, Friedenreich, CM, Gaudet, MM, Haiman, CA, Hankinson, SE, Hartge, P, Henderson, BE, Hong, YC, Hosgood, HD, Hsiung, CA, Hu, W, Hunter, DJ, Jessop, L, Kim, HN, Kim, YH, Kim, YT, Klein, R, Kraft, P, Lan, Q, Lin, D, Liu, J, Le Marchand, L, Liang, X, Lissowska, J, Lu, L, Magliocco, AM, Matsuo, K, Olson, SH, Orlow, I, Park, JY, Pooler, L, Prescott, J, Rastogi, R, Risch, HA, Schumacher, F, Seow, A, Setiawan, VW, Shen, H, Sheng, X, Shin, MH, Shu, XO, Vanden Berg, D, Wang, JC, Wentzensen, N, Wong, MP, Wu, C, Wu, T, Wu, YL, Xia, L, Yang, HP, Yang, PC, Zheng, W, Zhou, B, Abnet, CC, Albanes, D, Aldrich, MC, Amos, C, Amundadottir, LT, Berndt, SI, Blot, WJ, Bock, CH, Bracci, PM, Burdett, L, Buring, JE, Butler, MA, Carreón, T, Chatterjee, N, Chung, CC, Cook, MB, Cullen, M, Davis, FG, Ding, T, Duell, EJ, Epstein, CG, Fan, JH, Figueroa, JD, Fraumeni, JF, Freedman, ND, Fuchs, CS, Gao, YT, Gapstur, SM, Patiño-Garcia, A, Garcia-Closas, M, Gaziano, JM, Giles, GG, Gillanders, EM, Giovannucci, EL, Goldin, L, Goldstein, AM, Greene, MH, Hallmans, G, Harris, CC, Henriksson, R, Holly, EA, Hoover, RN, Hu, N, Hutchinson, A, Jenab, M, Johansen, C, Khaw, KT, Koh, WP, Kolonel, LN, Kooperberg, C, Krogh, V, Kurtz, RC, Lacroix, A, Landgren, A, Landi, MT, Li, D, Liao, LM, Malats, N, McGlynn, KA, McNeill, LH, McWilliams, RR, Melin, BS, Mirabello, L, Peplonska, B, Peters, U, Petersen, GM, Prokunina-Olsson, L, Purdue, M, Qiao, YL, Rabe, KG, Rajaraman, P, Real, FX, Riboli, E, Rodríguez-Santiago, B, Rothman, N, Ruder, AM, Savage, SA, Schwartz, AG, Schwartz, KL, Sesso, HD, Severi, G, Silverman, DT, Spitz, MR, Stevens, VL, Stolzenberg-Solomon, R, Stram, D, Tang, ZZ, Taylor, PR, Teras, LR, Tobias, GS, Viswanathan, K, Wacholder, S, Wang, Z, Weinstein, SJ, Wheeler, W, White, E, Wiencke, JK, Wolpin, BM, Wu, X, Wunder, JS, Yu, K, Zanetti, KA, Zeleniuch-Jacquotte, A, Ziegler, RG, De Andrade, M, Barnes, KC, Beaty, TL, Bierut, LJ, Desch, KC, Doheny, K, Feenstra, B, Ginsburg, D, Heit, JA, Kang, JH, Laurie, CA, Li, JZ, Lowe, WL, Marazita, ML, Melbye, M, Mirel, DB, Murray, JC, Nelson, SC, Pasquale, LR, Rice, K, Wiggs, JL, Wise, A, Tucker, M, Pérez-Jurado, LA, Laurie, CC, Caporaso, NE, Yeager, M & Chanock, SJ 2015, 'Characterization of large structural genetic mosaicism in human autosomes', American Journal of Human Genetics, vol. 96, no. 3, pp. 487-497. https://doi.org/10.1016/j.ajhg.2015.01.011
Machiela, Mitchell J. ; Zhou, Weiyin ; Sampson, Joshua N. ; Dean, Michael C. ; Jacobs, Kevin B. ; Black, Amanda ; Brinton, Louise A. ; Chang, I. Shou ; Chen, Chu ; Chen, Constance ; Chen, Kexin ; Cook, Linda S. ; Crous Bou, Marta ; De Vivo, Immaculata ; Doherty, Jennifer ; Friedenreich, Christine M. ; Gaudet, Mia M. ; Haiman, Christopher A. ; Hankinson, Susan E. ; Hartge, Patricia ; Henderson, Brian E. ; Hong, Yun Chul ; Hosgood, H. Dean ; Hsiung, Chao A. ; Hu, Wei ; Hunter, David J. ; Jessop, Lea ; Kim, Hee Nam ; Kim, Yeul Hong ; Kim, Young Tae ; Klein, Robert ; Kraft, Peter ; Lan, Qing ; Lin, Dongxin ; Liu, Jianjun ; Le Marchand, Loic ; Liang, Xiaolin ; Lissowska, Jolanta ; Lu, Lingeng ; Magliocco, Anthony M. ; Matsuo, Keitaro ; Olson, Sara H. ; Orlow, Irene ; Park, Jae Yong ; Pooler, Loreall ; Prescott, Jennifer ; Rastogi, Radhai ; Risch, Harvey A. ; Schumacher, Fredrick ; Seow, Adeline ; Setiawan, Veronica Wendy ; Shen, Hongbing ; Sheng, Xin ; Shin, Min Ho ; Shu, Xiao Ou ; Vanden Berg, David ; Wang, Jiu Cun ; Wentzensen, Nicolas ; Wong, Maria Pik ; Wu, Chen ; Wu, Tangchun ; Wu, Yi Long ; Xia, Lucy ; Yang, Hannah P. ; Yang, Pan Chyr ; Zheng, Wei ; Zhou, Baosen ; Abnet, Christian C. ; Albanes, Demetrius ; Aldrich, Melinda C. ; Amos, Christopher ; Amundadottir, Laufey T. ; Berndt, Sonja I. ; Blot, William J. ; Bock, Cathryn H. ; Bracci, Paige M. ; Burdett, Laurie ; Buring, Julie E. ; Butler, Mary A. ; Carreón, Tania ; Chatterjee, Nilanjan ; Chung, Charles C. ; Cook, Michael B. ; Cullen, Michael ; Davis, Faith G. ; Ding, Ti ; Duell, Eric J. ; Epstein, Caroline G. ; Fan, Jin Hu ; Figueroa, Jonine D. ; Fraumeni, Joseph F. ; Freedman, Neal D. ; Fuchs, Charles S. ; Gao, Yu Tang ; Gapstur, Susan M. ; Patiño-Garcia, Ana ; Garcia-Closas, Montserrat ; Gaziano, J. Michael ; Giles, Graham G. ; Gillanders, Elizabeth M. ; Giovannucci, Edward L. ; Goldin, Lynn ; Goldstein, Alisa M. ; Greene, Mark H. ; Hallmans, Goran ; Harris, Curtis C. ; Henriksson, Roger ; Holly, Elizabeth A. ; Hoover, Robert N. ; Hu, Nan ; Hutchinson, Amy ; Jenab, Mazda ; Johansen, Christoffer ; Khaw, Kay Tee ; Koh, Woon Puay ; Kolonel, Laurence N. ; Kooperberg, Charles ; Krogh, Vittorio ; Kurtz, Robert C. ; Lacroix, Andrea ; Landgren, Annelie ; Landi, Maria Teresa ; Li, Donghui ; Liao, Linda M. ; Malats, Nuria ; McGlynn, Katherine A. ; McNeill, Lorna H. ; McWilliams, Robert R. ; Melin, Beatrice S. ; Mirabello, Lisa ; Peplonska, Beata ; Peters, Ulrike ; Petersen, Gloria M. ; Prokunina-Olsson, Ludmila ; Purdue, Mark ; Qiao, You Lin ; Rabe, Kari G. ; Rajaraman, Preetha ; Real, Francisco X. ; Riboli, Elio ; Rodríguez-Santiago, Benjamín ; Rothman, Nathaniel ; Ruder, Avima M. ; Savage, Sharon A. ; Schwartz, Ann G. ; Schwartz, Kendra L. ; Sesso, Howard D. ; Severi, Gianluca ; Silverman, Debra T. ; Spitz, Margaret R. ; Stevens, Victoria L. ; Stolzenberg-Solomon, Rachael ; Stram, Daniel ; Tang, Ze Zhong ; Taylor, Philip R. ; Teras, Lauren R. ; Tobias, Geoffrey S. ; Viswanathan, Kala ; Wacholder, Sholom ; Wang, Zhaoming ; Weinstein, Stephanie J. ; Wheeler, William ; White, Emily ; Wiencke, John K. ; Wolpin, Brian M. ; Wu, Xifeng ; Wunder, Jay S. ; Yu, Kai ; Zanetti, Krista A. ; Zeleniuch-Jacquotte, Anne ; Ziegler, Regina G. ; De Andrade, Mariza ; Barnes, Kathleen C. ; Beaty, Terri L ; Bierut, Laura J. ; Desch, Karl C. ; Doheny, Kimberly ; Feenstra, Bjarke ; Ginsburg, David ; Heit, John A. ; Kang, Jae H. ; Laurie, Cecilia A. ; Li, Jun Z. ; Lowe, William L. ; Marazita, Mary L. ; Melbye, Mads ; Mirel, Daniel B. ; Murray, Jeffrey C. ; Nelson, Sarah C. ; Pasquale, Louis R. ; Rice, Kenneth ; Wiggs, Janey L. ; Wise, Anastasia ; Tucker, Margaret ; Pérez-Jurado, Luis A. ; Laurie, Cathy C. ; Caporaso, Neil E. ; Yeager, Meredith ; Chanock, Stephen J. / Characterization of large structural genetic mosaicism in human autosomes. In: American Journal of Human Genetics. 2015 ; Vol. 96, No. 3. pp. 487-497.
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title = "Characterization of large structural genetic mosaicism in human autosomes",
abstract = "Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68{\%}) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73{\%}] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10-31) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.",
author = "Machiela, {Mitchell J.} and Weiyin Zhou and Sampson, {Joshua N.} and Dean, {Michael C.} and Jacobs, {Kevin B.} and Amanda Black and Brinton, {Louise A.} and Chang, {I. Shou} and Chu Chen and Constance Chen and Kexin Chen and Cook, {Linda S.} and {Crous Bou}, Marta and {De Vivo}, Immaculata and Jennifer Doherty and Friedenreich, {Christine M.} and Gaudet, {Mia M.} and Haiman, {Christopher A.} and Hankinson, {Susan E.} and Patricia Hartge and Henderson, {Brian E.} and Hong, {Yun Chul} and Hosgood, {H. Dean} and Hsiung, {Chao A.} and Wei Hu and Hunter, {David J.} and Lea Jessop and Kim, {Hee Nam} and Kim, {Yeul Hong} and Kim, {Young Tae} and Robert Klein and Peter Kraft and Qing Lan and Dongxin Lin and Jianjun Liu and {Le Marchand}, Loic and Xiaolin Liang and Jolanta Lissowska and Lingeng Lu and Magliocco, {Anthony M.} and Keitaro Matsuo and Olson, {Sara H.} and Irene Orlow and Park, {Jae Yong} and Loreall Pooler and Jennifer Prescott and Radhai Rastogi and Risch, {Harvey A.} and Fredrick Schumacher and Adeline Seow and Setiawan, {Veronica Wendy} and Hongbing Shen and Xin Sheng and Shin, {Min Ho} and Shu, {Xiao Ou} and {Vanden Berg}, David and Wang, {Jiu Cun} and Nicolas Wentzensen and Wong, {Maria Pik} and Chen Wu and Tangchun Wu and Wu, {Yi Long} and Lucy Xia and Yang, {Hannah P.} and Yang, {Pan Chyr} and Wei Zheng and Baosen Zhou and Abnet, {Christian C.} and Demetrius Albanes and Aldrich, {Melinda C.} and Christopher Amos and Amundadottir, {Laufey T.} and Berndt, {Sonja I.} and Blot, {William J.} and Bock, {Cathryn H.} and Bracci, {Paige M.} and Laurie Burdett and Buring, {Julie E.} and Butler, {Mary A.} and Tania Carre{\'o}n and Nilanjan Chatterjee and Chung, {Charles C.} and Cook, {Michael B.} and Michael Cullen and Davis, {Faith G.} and Ti Ding and Duell, {Eric J.} and Epstein, {Caroline G.} and Fan, {Jin Hu} and Figueroa, {Jonine D.} and Fraumeni, {Joseph F.} and Freedman, {Neal D.} and Fuchs, {Charles S.} and Gao, {Yu Tang} and Gapstur, {Susan M.} and Ana Pati{\~n}o-Garcia and Montserrat Garcia-Closas and Gaziano, {J. Michael} and Giles, {Graham G.} and Gillanders, {Elizabeth M.} and Giovannucci, {Edward L.} and Lynn Goldin and Goldstein, {Alisa M.} and Greene, {Mark H.} and Goran Hallmans and Harris, {Curtis C.} and Roger Henriksson and Holly, {Elizabeth A.} and Hoover, {Robert N.} and Nan Hu and Amy Hutchinson and Mazda Jenab and Christoffer Johansen and Khaw, {Kay Tee} and Koh, {Woon Puay} and Kolonel, {Laurence N.} and Charles Kooperberg and Vittorio Krogh and Kurtz, {Robert C.} and Andrea Lacroix and Annelie Landgren and Landi, {Maria Teresa} and Donghui Li and Liao, {Linda M.} and Nuria Malats and McGlynn, {Katherine A.} and McNeill, {Lorna H.} and McWilliams, {Robert R.} and Melin, {Beatrice S.} and Lisa Mirabello and Beata Peplonska and Ulrike Peters and Petersen, {Gloria M.} and Ludmila Prokunina-Olsson and Mark Purdue and Qiao, {You Lin} and Rabe, {Kari G.} and Preetha Rajaraman and Real, {Francisco X.} and Elio Riboli and Benjam{\'i}n Rodr{\'i}guez-Santiago and Nathaniel Rothman and Ruder, {Avima M.} and Savage, {Sharon A.} and Schwartz, {Ann G.} and Schwartz, {Kendra L.} and Sesso, {Howard D.} and Gianluca Severi and Silverman, {Debra T.} and Spitz, {Margaret R.} and Stevens, {Victoria L.} and Rachael Stolzenberg-Solomon and Daniel Stram and Tang, {Ze Zhong} and Taylor, {Philip R.} and Teras, {Lauren R.} and Tobias, {Geoffrey S.} and Kala Viswanathan and Sholom Wacholder and Zhaoming Wang and Weinstein, {Stephanie J.} and William Wheeler and Emily White and Wiencke, {John K.} and Wolpin, {Brian M.} and Xifeng Wu and Wunder, {Jay S.} and Kai Yu and Zanetti, {Krista A.} and Anne Zeleniuch-Jacquotte and Ziegler, {Regina G.} and {De Andrade}, Mariza and Barnes, {Kathleen C.} and Beaty, {Terri L} and Bierut, {Laura J.} and Desch, {Karl C.} and Kimberly Doheny and Bjarke Feenstra and David Ginsburg and Heit, {John A.} and Kang, {Jae H.} and Laurie, {Cecilia A.} and Li, {Jun Z.} and Lowe, {William L.} and Marazita, {Mary L.} and Mads Melbye and Mirel, {Daniel B.} and Murray, {Jeffrey C.} and Nelson, {Sarah C.} and Pasquale, {Louis R.} and Kenneth Rice and Wiggs, {Janey L.} and Anastasia Wise and Margaret Tucker and P{\'e}rez-Jurado, {Luis A.} and Laurie, {Cathy C.} and Caporaso, {Neil E.} and Meredith Yeager and Chanock, {Stephen J.}",
year = "2015",
month = "3",
day = "5",
doi = "10.1016/j.ajhg.2015.01.011",
language = "English (US)",
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pages = "487--497",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",

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TY - JOUR

T1 - Characterization of large structural genetic mosaicism in human autosomes

AU - Machiela, Mitchell J.

AU - Zhou, Weiyin

AU - Sampson, Joshua N.

AU - Dean, Michael C.

AU - Jacobs, Kevin B.

AU - Black, Amanda

AU - Brinton, Louise A.

AU - Chang, I. Shou

AU - Chen, Chu

AU - Chen, Constance

AU - Chen, Kexin

AU - Cook, Linda S.

AU - Crous Bou, Marta

AU - De Vivo, Immaculata

AU - Doherty, Jennifer

AU - Friedenreich, Christine M.

AU - Gaudet, Mia M.

AU - Haiman, Christopher A.

AU - Hankinson, Susan E.

AU - Hartge, Patricia

AU - Henderson, Brian E.

AU - Hong, Yun Chul

AU - Hosgood, H. Dean

AU - Hsiung, Chao A.

AU - Hu, Wei

AU - Hunter, David J.

AU - Jessop, Lea

AU - Kim, Hee Nam

AU - Kim, Yeul Hong

AU - Kim, Young Tae

AU - Klein, Robert

AU - Kraft, Peter

AU - Lan, Qing

AU - Lin, Dongxin

AU - Liu, Jianjun

AU - Le Marchand, Loic

AU - Liang, Xiaolin

AU - Lissowska, Jolanta

AU - Lu, Lingeng

AU - Magliocco, Anthony M.

AU - Matsuo, Keitaro

AU - Olson, Sara H.

AU - Orlow, Irene

AU - Park, Jae Yong

AU - Pooler, Loreall

AU - Prescott, Jennifer

AU - Rastogi, Radhai

AU - Risch, Harvey A.

AU - Schumacher, Fredrick

AU - Seow, Adeline

AU - Setiawan, Veronica Wendy

AU - Shen, Hongbing

AU - Sheng, Xin

AU - Shin, Min Ho

AU - Shu, Xiao Ou

AU - Vanden Berg, David

AU - Wang, Jiu Cun

AU - Wentzensen, Nicolas

AU - Wong, Maria Pik

AU - Wu, Chen

AU - Wu, Tangchun

AU - Wu, Yi Long

AU - Xia, Lucy

AU - Yang, Hannah P.

AU - Yang, Pan Chyr

AU - Zheng, Wei

AU - Zhou, Baosen

AU - Abnet, Christian C.

AU - Albanes, Demetrius

AU - Aldrich, Melinda C.

AU - Amos, Christopher

AU - Amundadottir, Laufey T.

AU - Berndt, Sonja I.

AU - Blot, William J.

AU - Bock, Cathryn H.

AU - Bracci, Paige M.

AU - Burdett, Laurie

AU - Buring, Julie E.

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AU - Chanock, Stephen J.

PY - 2015/3/5

Y1 - 2015/3/5

N2 - Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10-31) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

AB - Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10-31) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

UR - http://www.scopus.com/inward/record.url?scp=84924140975&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924140975&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2015.01.011

DO - 10.1016/j.ajhg.2015.01.011

M3 - Article

VL - 96

SP - 487

EP - 497

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -