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 |
| DOIs | |
| Publication status | Published - 1 Dec 2020 |
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In: Nature Communications, Vol. 11, No. 1, 3353, 01.12.2020.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers
AU - Breast Cancer Association Consortium (BCAC)
AU - Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON)
AU - Colon Cancer Family Registry (CCFR)
AU - Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT)
AU - Endometrial Cancer Association Consortium (ECAC)
AU - Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO)
AU - Melanoma Genetics Consortium (GenoMEL)
AU - Glioma International Case-Control Study (GICC)
AU - International Lung Cancer Consortium (ILCCO)
AU - Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium
AU - International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph)
AU - Ovarian Cancer Association Consortium (OCAC)
AU - Oral Cancer GWAS
AU - Pancreatic Cancer Case-Control Consortium (PanC4)
AU - PanScan Consortium
AU - Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL)
AU - Renal Cancer GWAS
AU - Testicular Cancer Consortium (TECAC)
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 - 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 - 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 - 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 - Landi, Maria Teresa
AU - Law, Matthew H.
AU - Iles, Mark M.
AU - Demenais, Florence
AU - Kumar, Rajiv
AU - MacGregor, Stuart
AU - Bishop, David T.
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 - 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 - Amos, Christopher I.
AU - Brennan, Paul
AU - McKay, James
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 - 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 - Chanock, Stephen J.
AU - Chatterjee, Nilanjan
AU - Garcia-Closas, Montserrat
PY - 2020/12/1
Y1 - 2020/12/1
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.
UR - http://www.scopus.com/inward/record.url?scp=85087397990&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-16483-3
DO - 10.1038/s41467-020-16483-3
M3 - Article
C2 - 32620889
AN - SCOPUS:85087397990
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3353
ER -