Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Yan Dora Zhang; Amber N. Hurson; Haoyu Zhang; Parichoy Pal Choudhury; Douglas F. Easton; Roger L. Milne; Jacques Simard; Per Hall; Kyriaki Michailidou; Joe Dennis; Marjanka K. Schmidt; Jenny Chang-Claude; Puya Gharahkhani; David Whiteman; Peter T. Campbell; Michael Hoffmeister; Mark Jenkins; Ulrike Peters; Li Hsu; Stephen B. Gruber; Graham Casey; Stephanie L. Schmit; Tracy A. O’Mara; Amanda B. Spurdle; Deborah J. Thompson; Ian Tomlinson; Immaculata De Vivo; Maria Teresa Landi; Matthew H. Law; Mark M. Iles; Florence Demenais; Rajiv Kumar; Stuart MacGregor; D. Timothy Bishop; Sarah V. Ward; Melissa L. Bondy; Richard Houlston; John K. Wiencke; Beatrice Melin; Jill Barnholtz-Sloan; Ben Kinnersley; Margaret R. Wrensch; Christopher I. Amos; Rayjean J. Hung; Paul Brennan; James McKay; Neil E. Caporaso; Sonja I. Berndt; Brenda M. Birmann; Nicola J. Camp; Peter Kraft; Nathaniel Rothman; Susan L. Slager; Andrew Berchuck; Paul D.P. Pharoah; Thomas A. Sellers; Simon A. Gayther; Celeste L. Pearce; Ellen L. Goode; Joellen M. Schildkraut; Kirsten B. Moysich; Laufey T. Amundadottir; Eric J. Jacobs; Alison P. Klein; Gloria M. Petersen; Harvey A. Risch; Rachel Z. Stolzenberg-Solomon; Brian M. Wolpin; Donghui Li; Rosalind A. Eeles; Christopher A. Haiman; Zsofia Kote-Jarai; Fredrick R. Schumacher; Ali Amin Al Olama; Mark P. Purdue; Ghislaine Scelo; Marlene D. Dalgaard; Mark H. Greene; Tom Grotmol; Peter A. Kanetsky; Katherine A. McGlynn; Katherine L. Nathanson; Clare Turnbull; Fredrik Wiklund; David T. Bishop; Stephen J. Chanock; Nilanjan Chatterjee; Montserrat Garcia-Closas

doi:10.1038/s41467-020-16483-3

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Yan Dora Zhang, Amber N. Hurson, Haoyu Zhang, Parichoy Pal Choudhury, Douglas F. Easton, Roger L. Milne, Jacques Simard, Per Hall, Kyriaki Michailidou, Joe Dennis, Marjanka K. Schmidt, Jenny Chang-Claude, Puya Gharahkhani, David Whiteman, Peter T. Campbell, Michael Hoffmeister, Mark Jenkins, Ulrike Peters, Li Hsu, Stephen B. GruberGraham Casey, Stephanie L. Schmit, Tracy A. O’Mara, Amanda B. Spurdle, Deborah J. Thompson, Ian Tomlinson, Immaculata De Vivo, Maria Teresa Landi, Matthew H. Law, Mark M. Iles, Florence Demenais, Rajiv Kumar, Stuart MacGregor, D. Timothy Bishop, Sarah V. Ward, Melissa L. Bondy, Richard Houlston, John K. Wiencke, Beatrice Melin, Jill Barnholtz-Sloan, Ben Kinnersley, Margaret R. Wrensch, Christopher I. Amos, Rayjean J. Hung, Paul Brennan, James McKay, Neil E. Caporaso, Sonja I. Berndt, Brenda M. Birmann, Nicola J. Camp, Peter Kraft, Nathaniel Rothman, Susan L. Slager, Andrew Berchuck, Paul D.P. Pharoah, Thomas A. Sellers, Simon A. Gayther, Celeste L. Pearce, Ellen L. Goode, Joellen M. Schildkraut, Kirsten B. Moysich, Laufey T. Amundadottir, Eric J. Jacobs, Alison P. Klein, Gloria M. Petersen, Harvey A. Risch, Rachel Z. Stolzenberg-Solomon, Brian M. Wolpin, Donghui Li, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Ali Amin Al Olama, Mark P. Purdue, Ghislaine Scelo, Marlene D. Dalgaard, Mark H. Greene, Tom Grotmol, Peter A. Kanetsky, Katherine A. McGlynn, Katherine L. Nathanson, Clare Turnbull, Fredrik Wiklund, David T. Bishop, Stephen J. Chanock, Nilanjan Chatterjee, Montserrat Garcia-Closas

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Abstract

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

Original language	English
Article number	3353
Journal	Nature Communications
Volume	11
Issue number	1
Number of pages	13
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-020-16483-3
Publication status	Published - 2020

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Zhang, Y. D., Hurson, A. N., Zhang, H., Choudhury, P. P., Easton, D. F., Milne, R. L., Simard, J., Hall, P., Michailidou, K., Dennis, J., Schmidt, M. K., Chang-Claude, J., Gharahkhani, P., Whiteman, D., Campbell, P. T., Hoffmeister, M., Jenkins, M., Peters, U., Hsu, L., ... Garcia-Closas, M. (2020). Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers. Nature Communications, 11(1), [3353]. https://doi.org/10.1038/s41467-020-16483-3

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title = "Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers",

abstract = "Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.",

author = "Zhang, {Yan Dora} and Hurson, {Amber N.} and Haoyu Zhang and Choudhury, {Parichoy Pal} and Easton, {Douglas F.} and Milne, {Roger L.} and Jacques Simard and Per Hall and Kyriaki Michailidou and Joe Dennis and Schmidt, {Marjanka K.} and Jenny Chang-Claude and Puya Gharahkhani and David Whiteman and Campbell, {Peter T.} and Michael Hoffmeister and Mark Jenkins and Ulrike Peters and Li Hsu and Gruber, {Stephen B.} and Graham Casey and Schmit, {Stephanie L.} and O{\textquoteright}Mara, {Tracy A.} and Spurdle, {Amanda B.} and Thompson, {Deborah J.} and Ian Tomlinson and {De Vivo}, Immaculata and Landi, {Maria Teresa} and Law, {Matthew H.} and Iles, {Mark M.} and Florence Demenais and Rajiv Kumar and Stuart MacGregor and Bishop, {D. Timothy} and Ward, {Sarah V.} and Bondy, {Melissa L.} and Richard Houlston and Wiencke, {John K.} and Beatrice Melin and Jill Barnholtz-Sloan and Ben Kinnersley and Wrensch, {Margaret R.} and Amos, {Christopher I.} and Hung, {Rayjean J.} and Paul Brennan and James McKay and Caporaso, {Neil E.} and Berndt, {Sonja I.} and Birmann, {Brenda M.} and Camp, {Nicola J.} and Peter Kraft and Nathaniel Rothman and Slager, {Susan L.} and Andrew Berchuck and Pharoah, {Paul D.P.} and Sellers, {Thomas A.} and Gayther, {Simon A.} and Pearce, {Celeste L.} and Goode, {Ellen L.} and Schildkraut, {Joellen M.} and Moysich, {Kirsten B.} and Amundadottir, {Laufey T.} and Jacobs, {Eric J.} and Klein, {Alison P.} and Petersen, {Gloria M.} and Risch, {Harvey A.} and Stolzenberg-Solomon, {Rachel Z.} and Wolpin, {Brian M.} and Donghui Li and Eeles, {Rosalind A.} and Haiman, {Christopher A.} and Zsofia Kote-Jarai and Schumacher, {Fredrick R.} and {Al Olama}, {Ali Amin} and Purdue, {Mark P.} and Ghislaine Scelo and Dalgaard, {Marlene D.} and Greene, {Mark H.} and Tom Grotmol and Kanetsky, {Peter A.} and McGlynn, {Katherine A.} and Nathanson, {Katherine L.} and Clare Turnbull and Fredrik Wiklund and Bishop, {David T.} and Chanock, {Stephen J.} and Nilanjan Chatterjee and Montserrat Garcia-Closas",

year = "2020",

doi = "10.1038/s41467-020-16483-3",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Zhang, YD, Hurson, AN, Zhang, H, Choudhury, PP, Easton, DF, Milne, RL, Simard, J, Hall, P, Michailidou, K, Dennis, J, Schmidt, MK, Chang-Claude, J, Gharahkhani, P, Whiteman, D, Campbell, PT, Hoffmeister, M, Jenkins, M, Peters, U, Hsu, L, Gruber, SB, Casey, G, Schmit, SL, O’Mara, TA, Spurdle, AB, Thompson, DJ, Tomlinson, I, De Vivo, I, Landi, MT, Law, MH, Iles, MM, Demenais, F, Kumar, R, MacGregor, S, Bishop, DT, Ward, SV, Bondy, ML, Houlston, R, Wiencke, JK, Melin, B, Barnholtz-Sloan, J, Kinnersley, B, Wrensch, MR, Amos, CI, Hung, RJ, Brennan, P, McKay, J, Caporaso, NE, Berndt, SI, Birmann, BM, Camp, NJ, Kraft, P, Rothman, N, Slager, SL, Berchuck, A, Pharoah, PDP, Sellers, TA, Gayther, SA, Pearce, CL, Goode, EL, Schildkraut, JM, Moysich, KB, Amundadottir, LT, Jacobs, EJ, Klein, AP, Petersen, GM, Risch, HA, Stolzenberg-Solomon, RZ, Wolpin, BM, Li, D, Eeles, RA, Haiman, CA, Kote-Jarai, Z, Schumacher, FR, Al Olama, AA, Purdue, MP, Scelo, G, Dalgaard, MD, Greene, MH, Grotmol, T, Kanetsky, PA, McGlynn, KA, Nathanson, KL, Turnbull, C, Wiklund, F, Bishop, DT, Chanock, SJ, Chatterjee, N & Garcia-Closas, M 2020, 'Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers', Nature Communications, vol. 11, no. 1, 3353. https://doi.org/10.1038/s41467-020-16483-3

TY - JOUR

T1 - Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

AU - Zhang, Yan Dora

AU - Hurson, Amber N.

AU - Zhang, Haoyu

AU - Choudhury, Parichoy Pal

AU - Easton, Douglas F.

AU - Milne, Roger L.

AU - Simard, Jacques

AU - Hall, Per

AU - Michailidou, Kyriaki

AU - Dennis, Joe

AU - Schmidt, Marjanka K.

AU - Chang-Claude, Jenny

AU - Gharahkhani, Puya

AU - Whiteman, David

AU - Campbell, Peter T.

AU - Hoffmeister, Michael

AU - Jenkins, Mark

AU - Peters, Ulrike

AU - Hsu, Li

AU - Gruber, Stephen B.

AU - Casey, Graham

AU - Schmit, Stephanie L.

AU - O’Mara, Tracy A.

AU - Spurdle, Amanda B.

AU - Thompson, Deborah J.

AU - Tomlinson, Ian

AU - De Vivo, Immaculata

AU - Landi, Maria Teresa

AU - Law, Matthew H.

AU - Iles, Mark M.

AU - Demenais, Florence

AU - Kumar, Rajiv

AU - MacGregor, Stuart

AU - Bishop, D. Timothy

AU - Ward, Sarah V.

AU - Bondy, Melissa L.

AU - Houlston, Richard

AU - Wiencke, John K.

AU - Melin, Beatrice

AU - Barnholtz-Sloan, Jill

AU - Kinnersley, Ben

AU - Wrensch, Margaret R.

AU - Amos, Christopher I.

AU - Hung, Rayjean J.

AU - Brennan, Paul

AU - McKay, James

AU - Caporaso, Neil E.

AU - Berndt, Sonja I.

AU - Birmann, Brenda M.

AU - Camp, Nicola J.

AU - Kraft, Peter

AU - Rothman, Nathaniel

AU - Slager, Susan L.

AU - Berchuck, Andrew

AU - Pharoah, Paul D.P.

AU - Sellers, Thomas A.

AU - Gayther, Simon A.

AU - Pearce, Celeste L.

AU - Goode, Ellen L.

AU - Schildkraut, Joellen M.

AU - Moysich, Kirsten B.

AU - Amundadottir, Laufey T.

AU - Jacobs, Eric J.

AU - Klein, Alison P.

AU - Petersen, Gloria M.

AU - Risch, Harvey A.

AU - Stolzenberg-Solomon, Rachel Z.

AU - Wolpin, Brian M.

AU - Li, Donghui

AU - Eeles, Rosalind A.

AU - Haiman, Christopher A.

AU - Kote-Jarai, Zsofia

AU - Schumacher, Fredrick R.

AU - Al Olama, Ali Amin

AU - Purdue, Mark P.

AU - Scelo, Ghislaine

AU - Dalgaard, Marlene D.

AU - Greene, Mark H.

AU - Grotmol, Tom

AU - Kanetsky, Peter A.

AU - McGlynn, Katherine A.

AU - Nathanson, Katherine L.

AU - Turnbull, Clare

AU - Wiklund, Fredrik

AU - Bishop, David T.

AU - Chanock, Stephen J.

AU - Chatterjee, Nilanjan

AU - Garcia-Closas, Montserrat

PY - 2020

Y1 - 2020

N2 - Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

AB - Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.

U2 - 10.1038/s41467-020-16483-3

DO - 10.1038/s41467-020-16483-3

M3 - Journal article

C2 - 32620889

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3353

ER -

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

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