Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions

Ying Han; Dennis J. Hazelett; Fredrik Wiklund; Fredrick R. Schumacher; Daniel O. Stram; Sonja I. Berndt; Zhaoming Wang; Kristin A. Rand; Robert N. Hoover; Mitchell J. Machiela; Merideth Yeager; Laurie Burdette; Charles C. Chung; Amy Hutchinson; Kai Yu; Jianfeng Xu; Ruth C. Travis; Timothy J. Key; Afshan Siddiq; Federico Canzian; Atsushi Takahashi; Michiaki Kubo; Janet L. Stanford; Suzanne Kolb; Susan M. Gapstur; W. Ryan Diver; Victoria L. Stevens; Sara S. Strom; Curtis A. Pettaway; Ali Amin Al Olama; Zsofia Kote-Jarai; Rosalind A. Eeles; Edward D. Yeboah; Yao Tettey; Richard B. Biritwum; Andrew A. Adjei; Evelyn Tay; Ann Truelove; Shelley Niwa; Anand P. Chokkalingam; William B. Isaacs; Constance Chen; Sara Lindstrom; Loic Le Marchand; Edward L. Giovannucci; Mark Pomerantz; Henry Long; Fugen Li; Jing Ma; Meir Stampfer; Esther M. John; Sue A. Ingles; Rick A. Kittles; Adam B. Murphy; William J. Blot; Lisa B. Signorello; Wei Zheng; Demetrius Albanes; Jarmo Virtamo; Stephanie Weinstein; Barbara Nemesure; John Carpten; M. Cristina Leske; Suh Yuh Wu; Anselm J.M. Hennis; Benjamin A. Rybicki; Christine Neslund-Dudas; Ann W. Hsing; Lisa Chu; Phyllis J. Goodman; Eric A. Klein; S. Lilly Zheng; John S. Witte; Graham Casey; Elio Riboli; Qiyuan Li; Matthew L. Freedman; David J. Hunter; Henrik Gronberg; Michael B. Cook; Hidewaki Nakagawa; Peter Kraft; Stephen J. Chanock; Douglas F. Easton; Brian E. Henderson; Gerhard A. Coetzee; David V. Conti; Christopher A. Haiman

doi:10.1093/hmg/ddv269

Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions

Ying Han, Dennis J. Hazelett, Fredrik Wiklund, Fredrick R. Schumacher, Daniel O. Stram, Sonja I. Berndt, Zhaoming Wang, Kristin A. Rand, Robert N. Hoover, Mitchell J. Machiela, Merideth Yeager, Laurie Burdette, Charles C. Chung, Amy Hutchinson, Kai Yu, Jianfeng Xu, Ruth C. Travis, Timothy J. Key, Afshan Siddiq, Federico CanzianAtsushi Takahashi, Michiaki Kubo, Janet L. Stanford, Suzanne Kolb, Susan M. Gapstur, W. Ryan Diver, Victoria L. Stevens, Sara S. Strom, Curtis A. Pettaway, Ali Amin Al Olama, Zsofia Kote-Jarai, Rosalind A. Eeles, Edward D. Yeboah, Yao Tettey, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Anand P. Chokkalingam, William B. Isaacs, Constance Chen, Sara Lindstrom, Loic Le Marchand, Edward L. Giovannucci, Mark Pomerantz, Henry Long, Fugen Li, Jing Ma, Meir Stampfer, Esther M. John, Sue A. Ingles, Rick A. Kittles, Adam B. Murphy, William J. Blot, Lisa B. Signorello, Wei Zheng, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Barbara Nemesure, John Carpten, M. Cristina Leske, Suh Yuh Wu, Anselm J.M. Hennis, Benjamin A. Rybicki, Christine Neslund-Dudas, Ann W. Hsing, Lisa Chu, Phyllis J. Goodman, Eric A. Klein, S. Lilly Zheng, John S. Witte, Graham Casey, Elio Riboli, Qiyuan Li, Matthew L. Freedman, David J. Hunter, Henrik Gronberg, Michael B. Cook, Hidewaki Nakagawa, Peter Kraft, Stephen J. Chanock, Douglas F. Easton, Brian E. Henderson, Gerhard A. Coetzee, David V. Conti, Christopher A. Haiman

School of Medicine

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genomeencoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10^-4-5.6 × 10^-3) and in 30 regions we identified markers thatwere more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10^-6) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

Original language	English (US)
Pages (from-to)	5603-5618
Number of pages	16
Journal	Human molecular genetics
Volume	24
Issue number	19
DOIs	https://doi.org/10.1093/hmg/ddv269
State	Published - Oct 1 2015

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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Han, Y., Hazelett, D. J., Wiklund, F., Schumacher, F. R., Stram, D. O., Berndt, S. I., Wang, Z., Rand, K. A., Hoover, R. N., Machiela, M. J., Yeager, M., Burdette, L., Chung, C. C., Hutchinson, A., Yu, K., Xu, J., Travis, R. C., Key, T. J., Siddiq, A., ... Haiman, C. A. (2015). Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions. Human molecular genetics, 24(19), 5603-5618. https://doi.org/10.1093/hmg/ddv269

Han, Y, Hazelett, DJ, Wiklund, F, Schumacher, FR, Stram, DO, Berndt, SI, Wang, Z, Rand, KA, Hoover, RN, Machiela, MJ, Yeager, M, Burdette, L, Chung, CC, Hutchinson, A, Yu, K, Xu, J, Travis, RC, Key, TJ, Siddiq, A, Canzian, F, Takahashi, A, Kubo, M, Stanford, JL, Kolb, S, Gapstur, SM, Ryan Diver, W, Stevens, VL, Strom, SS, Pettaway, CA, Al Olama, AA, Kote-Jarai, Z, Eeles, RA, Yeboah, ED, Tettey, Y, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Chokkalingam, AP, Isaacs, WB, Chen, C, Lindstrom, S, Le Marchand, L, Giovannucci, EL, Pomerantz, M, Long, H, Li, F, Ma, J, Stampfer, M, John, EM, Ingles, SA, Kittles, RA, Murphy, AB, Blot, WJ, Signorello, LB, Zheng, W, Albanes, D, Virtamo, J, Weinstein, S, Nemesure, B, Carpten, J, Cristina Leske, M, Wu, SY, Hennis, AJM, Rybicki, BA, Neslund-Dudas, C, Hsing, AW, Chu, L, Goodman, PJ, Klein, EA, Lilly Zheng, S, Witte, JS, Casey, G, Riboli, E, Li, Q, Freedman, ML, Hunter, DJ, Gronberg, H, Cook, MB, Nakagawa, H, Kraft, P, Chanock, SJ, Easton, DF, Henderson, BE, Coetzee, GA, Conti, DV & Haiman, CA 2015, 'Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions', Human molecular genetics, vol. 24, no. 19, pp. 5603-5618. https://doi.org/10.1093/hmg/ddv269

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title = "Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions",

abstract = "Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genomeencoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10-4-5.6 × 10-3) and in 30 regions we identified markers thatwere more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10-6) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.",

author = "Ying Han and Hazelett, {Dennis J.} and Fredrik Wiklund and Schumacher, {Fredrick R.} and Stram, {Daniel O.} and Berndt, {Sonja I.} and Zhaoming Wang and Rand, {Kristin A.} and Hoover, {Robert N.} and Machiela, {Mitchell J.} and Merideth Yeager and Laurie Burdette and Chung, {Charles C.} and Amy Hutchinson and Kai Yu and Jianfeng Xu and Travis, {Ruth C.} and Key, {Timothy J.} and Afshan Siddiq and Federico Canzian and Atsushi Takahashi and Michiaki Kubo and Stanford, {Janet L.} and Suzanne Kolb and Gapstur, {Susan M.} and {Ryan Diver}, W. and Stevens, {Victoria L.} and Strom, {Sara S.} and Pettaway, {Curtis A.} and {Al Olama}, {Ali Amin} and Zsofia Kote-Jarai and Eeles, {Rosalind A.} and Yeboah, {Edward D.} and Yao Tettey and Biritwum, {Richard B.} and Adjei, {Andrew A.} and Evelyn Tay and Ann Truelove and Shelley Niwa and Chokkalingam, {Anand P.} and Isaacs, {William B.} and Constance Chen and Sara Lindstrom and {Le Marchand}, Loic and Giovannucci, {Edward L.} and Mark Pomerantz and Henry Long and Fugen Li and Jing Ma and Meir Stampfer and John, {Esther M.} and Ingles, {Sue A.} and Kittles, {Rick A.} and Murphy, {Adam B.} and Blot, {William J.} and Signorello, {Lisa B.} and Wei Zheng and Demetrius Albanes and Jarmo Virtamo and Stephanie Weinstein and Barbara Nemesure and John Carpten and {Cristina Leske}, M. and Wu, {Suh Yuh} and Hennis, {Anselm J.M.} and Rybicki, {Benjamin A.} and Christine Neslund-Dudas and Hsing, {Ann W.} and Lisa Chu and Goodman, {Phyllis J.} and Klein, {Eric A.} and {Lilly Zheng}, S. and Witte, {John S.} and Graham Casey and Elio Riboli and Qiyuan Li and Freedman, {Matthew L.} and Hunter, {David J.} and Henrik Gronberg and Cook, {Michael B.} and Hidewaki Nakagawa and Peter Kraft and Chanock, {Stephen J.} and Easton, {Douglas F.} and Henderson, {Brian E.} and Coetzee, {Gerhard A.} and Conti, {David V.} and Haiman, {Christopher A.}",

year = "2015",

month = oct,

day = "1",

doi = "10.1093/hmg/ddv269",

language = "English (US)",

volume = "24",

pages = "5603--5618",

journal = "Human molecular genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "19",

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TY - JOUR

T1 - Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions

AU - Han, Ying

AU - Hazelett, Dennis J.

AU - Wiklund, Fredrik

AU - Schumacher, Fredrick R.

AU - Stram, Daniel O.

AU - Berndt, Sonja I.

AU - Wang, Zhaoming

AU - Rand, Kristin A.

AU - Hoover, Robert N.

AU - Machiela, Mitchell J.

AU - Yeager, Merideth

AU - Burdette, Laurie

AU - Chung, Charles C.

AU - Hutchinson, Amy

AU - Yu, Kai

AU - Xu, Jianfeng

AU - Travis, Ruth C.

AU - Key, Timothy J.

AU - Siddiq, Afshan

AU - Canzian, Federico

AU - Takahashi, Atsushi

AU - Kubo, Michiaki

AU - Stanford, Janet L.

AU - Kolb, Suzanne

AU - Gapstur, Susan M.

AU - Ryan Diver, W.

AU - Stevens, Victoria L.

AU - Strom, Sara S.

AU - Pettaway, Curtis A.

AU - Al Olama, Ali Amin

AU - Kote-Jarai, Zsofia

AU - Eeles, Rosalind A.

AU - Yeboah, Edward D.

AU - Tettey, Yao

AU - Biritwum, Richard B.

AU - Adjei, Andrew A.

AU - Tay, Evelyn

AU - Truelove, Ann

AU - Niwa, Shelley

AU - Chokkalingam, Anand P.

AU - Isaacs, William B.

AU - Chen, Constance

AU - Lindstrom, Sara

AU - Le Marchand, Loic

AU - Giovannucci, Edward L.

AU - Pomerantz, Mark

AU - Long, Henry

AU - Li, Fugen

AU - Ma, Jing

AU - Stampfer, Meir

AU - John, Esther M.

AU - Ingles, Sue A.

AU - Kittles, Rick A.

AU - Murphy, Adam B.

AU - Blot, William J.

AU - Signorello, Lisa B.

AU - Zheng, Wei

AU - Albanes, Demetrius

AU - Virtamo, Jarmo

AU - Weinstein, Stephanie

AU - Nemesure, Barbara

AU - Carpten, John

AU - Cristina Leske, M.

AU - Wu, Suh Yuh

AU - Hennis, Anselm J.M.

AU - Rybicki, Benjamin A.

AU - Neslund-Dudas, Christine

AU - Hsing, Ann W.

AU - Chu, Lisa

AU - Goodman, Phyllis J.

AU - Klein, Eric A.

AU - Lilly Zheng, S.

AU - Witte, John S.

AU - Casey, Graham

AU - Riboli, Elio

AU - Li, Qiyuan

AU - Freedman, Matthew L.

AU - Hunter, David J.

AU - Gronberg, Henrik

AU - Cook, Michael B.

AU - Nakagawa, Hidewaki

AU - Kraft, Peter

AU - Chanock, Stephen J.

AU - Easton, Douglas F.

AU - Henderson, Brian E.

AU - Coetzee, Gerhard A.

AU - Conti, David V.

AU - Haiman, Christopher A.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genomeencoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10-4-5.6 × 10-3) and in 30 regions we identified markers thatwere more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10-6) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

AB - Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genomeencoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10-4-5.6 × 10-3) and in 30 regions we identified markers thatwere more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10-6) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.

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ER -

Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions

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