Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Alexander Gusev; Huwenbo Shi; Gleb Kichaev; Mark Pomerantz; Fugen Li; Henry W Long; Sue A Ingles; Rick A Kittles; Sara S Strom; Benjamin A Rybicki; Barbara Nemesure; William B Isaacs; Wei Zheng; Curtis A Pettaway; Edward D Yeboah; Yao Tettey; Richard B Biritwum; Andrew A Adjei; Evelyn Tay; Ann Truelove; Shelley Niwa; Anand P Chokkalingam; Esther M John; Adam B Murphy; Lisa B Signorello; John Carpten; M Cristina Leske; Suh-Yuh Wu; Anslem J M Hennis; Christine Neslund-Dudas; Ann W Hsing; Lisa Chu; Phyllis J Goodman; Eric A Klein; John S Witte; Graham Casey; Sam Kaggwa; Michael B Cook; Daniel O Stram; William J Blot; Rosalind A Eeles; Douglas Easton; Zsofia Kote-Jarai; Ali Amin Al Olama; Sara Benlloch; Kenneth Muir; Graham Giles; Melissa C Southey; Liesel M Fitzgerald; Børge G Nordestgaard; PRACTICAL consortium

doi:10.1038/ncomms10979

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Alexander Gusev, Huwenbo Shi, Gleb Kichaev, Mark Pomerantz, Fugen Li, Henry W Long, Sue A Ingles, Rick A Kittles, Sara S Strom, Benjamin A Rybicki, Barbara Nemesure, William B Isaacs, Wei Zheng, Curtis A Pettaway, Edward D Yeboah, Yao Tettey, Richard B Biritwum, Andrew A Adjei, Evelyn Tay, Ann TrueloveShelley Niwa, Anand P Chokkalingam, Esther M John, Adam B Murphy, Lisa B Signorello, John Carpten, M Cristina Leske, Suh-Yuh Wu, Anslem J M Hennis, Christine Neslund-Dudas, Ann W Hsing, Lisa Chu, Phyllis J Goodman, Eric A Klein, John S Witte, Graham Casey, Sam Kaggwa, Michael B Cook, Daniel O Stram, William J Blot, Rosalind A Eeles, Douglas Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham Giles, Melissa C Southey, Liesel M Fitzgerald, Børge G Nordestgaard, PRACTICAL consortium

Department of Clinical Medicine

30 Citations (Scopus)

Abstract

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Original language	English
Article number	10979
Journal	Nature Communications
Volume	7
Pages (from-to)	1-13
Number of pages	13
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms10979
Publication status	Published - 7 Apr 2016

Keywords

Acetylation
African Americans
Atlases as Topic
Cell Line, Tumor
Epigenesis, Genetic
European Continental Ancestry Group
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Histones
Humans
Inheritance Patterns
Linkage Disequilibrium
Male
Polymorphism, Single Nucleotide
Prostatic Neoplasms
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms10979

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Gusev, A., Shi, H., Kichaev, G., Pomerantz, M., Li, F., Long, H. W., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Zheng, W., Pettaway, C. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., ... PRACTICAL consortium (2016). Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation. Nature Communications, 7, 1-13. [10979]. https://doi.org/10.1038/ncomms10979

Gusev, A, Shi, H, Kichaev, G, Pomerantz, M, Li, F, Long, HW, 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, S-Y, Hennis, AJM, Neslund-Dudas, C, Hsing, AW, Chu, L, Goodman, PJ, Klein, EA, Witte, JS, Casey, G, Kaggwa, S, Cook, MB, Stram, DO, Blot, WJ, Eeles, RA, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, G, Southey, MC, Fitzgerald, LM, Nordestgaard, BG & PRACTICAL consortium 2016, 'Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation', Nature Communications, vol. 7, 10979, pp. 1-13. https://doi.org/10.1038/ncomms10979

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title = "Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation",

abstract = "Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.",

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author = "Alexander Gusev and Huwenbo Shi and Gleb Kichaev and Mark Pomerantz and Fugen Li and Long, {Henry W} and Ingles, {Sue A} and Kittles, {Rick A} and Strom, {Sara S} and Rybicki, {Benjamin A} and Barbara Nemesure and Isaacs, {William B} and Wei Zheng and Pettaway, {Curtis 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 John, {Esther M} and Murphy, {Adam B} and Signorello, {Lisa B} and John Carpten and Leske, {M Cristina} and Suh-Yuh Wu and Hennis, {Anslem J M} and Christine Neslund-Dudas and Hsing, {Ann W} and Lisa Chu and Goodman, {Phyllis J} and Klein, {Eric A} and Witte, {John S} and Graham Casey and Sam Kaggwa and Cook, {Michael B} and Stram, {Daniel O} and Blot, {William J} and Eeles, {Rosalind A} and Douglas Easton and Zsofia Kote-Jarai and {Al Olama}, {Ali Amin} and Sara Benlloch and Kenneth Muir and Graham Giles and Southey, {Melissa C} and Fitzgerald, {Liesel M} and Nordestgaard, {B{\o}rge G} and {PRACTICAL consortium}",

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doi = "10.1038/ncomms10979",

language = "English",

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journal = "Nature Communications",

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T1 - Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

AU - Gusev, Alexander

AU - Shi, Huwenbo

AU - Kichaev, Gleb

AU - Pomerantz, Mark

AU - Li, Fugen

AU - Long, Henry W

AU - Ingles, Sue A

AU - Kittles, Rick A

AU - Strom, Sara S

AU - Rybicki, Benjamin A

AU - Nemesure, Barbara

AU - Isaacs, William B

AU - Zheng, Wei

AU - Pettaway, Curtis 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 - John, Esther M

AU - Murphy, Adam B

AU - Signorello, Lisa B

AU - Carpten, John

AU - Leske, M Cristina

AU - Wu, Suh-Yuh

AU - Hennis, Anslem J M

AU - Neslund-Dudas, Christine

AU - Hsing, Ann W

AU - Chu, Lisa

AU - Goodman, Phyllis J

AU - Klein, Eric A

AU - Witte, John S

AU - Casey, Graham

AU - Kaggwa, Sam

AU - Cook, Michael B

AU - Stram, Daniel O

AU - Blot, William J

AU - Eeles, Rosalind A

AU - Easton, Douglas

AU - Kote-Jarai, Zsofia

AU - Al Olama, Ali Amin

AU - Benlloch, Sara

AU - Muir, Kenneth

AU - Giles, Graham

AU - Southey, Melissa C

AU - Fitzgerald, Liesel M

AU - Nordestgaard, Børge G

AU - PRACTICAL consortium

PY - 2016/4/7

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N2 - Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

AB - Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

KW - Acetylation

KW - African Americans

KW - Atlases as Topic

KW - Cell Line, Tumor

KW - Epigenesis, Genetic

KW - European Continental Ancestry Group

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Histones

KW - Humans

KW - Inheritance Patterns

KW - Linkage Disequilibrium

KW - Male

KW - Polymorphism, Single Nucleotide

KW - Prostatic Neoplasms

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

U2 - 10.1038/ncomms10979

DO - 10.1038/ncomms10979

M3 - Journal article

C2 - 27052111

SN - 2041-1723

VL - 7

SP - 1

EP - 13

JO - Nature Communications

JF - Nature Communications

M1 - 10979

ER -

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Abstract

Keywords

UN SDGs

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