Family-based association analysis of 42 hereditary prostate cancer families identifies the Apolipoprotein L3 region on chromosome 22q12 as a risk locus

Bo Johanneson, Shannon K. McDonnell, Danielle M. Karyadi, Pascale Quignon, Laura McIntosh, Shaun M. Riska, Liesel M. FitzGerald, Gregory Johnson, Kerry Deutsch, Gabrielle Williams, Lori S. Tillmans, Janet L. Stanford, Daniel J Schaid, Stephen N Thibodeau, Elaine A. Ostrander

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Abstract

Multiple genome-wide scans for hereditary prostate cancer (HPC) have identified susceptibility loci on nearly every chromosome. However, few results have been replicated with statistical significance. One exception is chromosome 22q, for which five independent linkage studies yielded strong evidence for a susceptibility locus in HPC families. Previously, we refined this region to a 2.53 Mb interval, using recombination mapping in 42 linked pedigrees. We now refine this locus to a 15 kb interval, spanning Apolipoprotein L3 (APOL3), using family-based association analyses of 150 total prostate cancer (PC) cases from two independent family collections with 506 unrelated population controls. Analysis of the two independent sets of PC cases highlighted single nucleotide polymorphisms (SNPs) within the APOL3 locus showing the strongest associations with HPC risk, with the most robust results observed when all 150 cases were combined. Analysis of 15 tagSNPs across the 5′ end of the locus identified six SNPs with P-values ≤2 × 10-4. The two independent sets of HPC cases highlight the same 15 kb interval at the 5′ end of the APOL3 gene and provide strong evidence that SNPs within this 15 kb interval, or in strong linkage disequilibrium with it, contribute to HPC risk. Further analyses of this locus in an independent population-based, case-control study revealed an association between an SNP within the APOL3 locus and PC risk, which was not confirmed in the Cancer Genetic Markers of Susceptibility data set. This study further characterizes the 22q locus in HPC risk and suggests that the role of this region in sporadic PC warrants additional studies. Published by Oxford University Press 2010.

Original languageEnglish (US)
Article numberddq283
Pages (from-to)3852-3862
Number of pages11
JournalHuman Molecular Genetics
Volume19
Issue number19
DOIs
StatePublished - Jul 14 2010

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Apolipoproteins
Chromosomes
Single Nucleotide Polymorphism
Prostatic Neoplasms
Population Control
Linkage Disequilibrium
Pedigree
Genetic Predisposition to Disease
Genetic Markers
Genetic Recombination
Familial Prostate cancer
Case-Control Studies
Genome
Population
Genes
Neoplasms

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Johanneson, B., McDonnell, S. K., Karyadi, D. M., Quignon, P., McIntosh, L., Riska, S. M., ... Ostrander, E. A. (2010). Family-based association analysis of 42 hereditary prostate cancer families identifies the Apolipoprotein L3 region on chromosome 22q12 as a risk locus. Human Molecular Genetics, 19(19), 3852-3862. [ddq283]. https://doi.org/10.1093/hmg/ddq283

Family-based association analysis of 42 hereditary prostate cancer families identifies the Apolipoprotein L3 region on chromosome 22q12 as a risk locus. / Johanneson, Bo; McDonnell, Shannon K.; Karyadi, Danielle M.; Quignon, Pascale; McIntosh, Laura; Riska, Shaun M.; FitzGerald, Liesel M.; Johnson, Gregory; Deutsch, Kerry; Williams, Gabrielle; Tillmans, Lori S.; Stanford, Janet L.; Schaid, Daniel J; Thibodeau, Stephen N; Ostrander, Elaine A.

In: Human Molecular Genetics, Vol. 19, No. 19, ddq283, 14.07.2010, p. 3852-3862.

Research output: Contribution to journalArticle

Johanneson, B, McDonnell, SK, Karyadi, DM, Quignon, P, McIntosh, L, Riska, SM, FitzGerald, LM, Johnson, G, Deutsch, K, Williams, G, Tillmans, LS, Stanford, JL, Schaid, DJ, Thibodeau, SN & Ostrander, EA 2010, 'Family-based association analysis of 42 hereditary prostate cancer families identifies the Apolipoprotein L3 region on chromosome 22q12 as a risk locus', Human Molecular Genetics, vol. 19, no. 19, ddq283, pp. 3852-3862. https://doi.org/10.1093/hmg/ddq283
Johanneson, Bo ; McDonnell, Shannon K. ; Karyadi, Danielle M. ; Quignon, Pascale ; McIntosh, Laura ; Riska, Shaun M. ; FitzGerald, Liesel M. ; Johnson, Gregory ; Deutsch, Kerry ; Williams, Gabrielle ; Tillmans, Lori S. ; Stanford, Janet L. ; Schaid, Daniel J ; Thibodeau, Stephen N ; Ostrander, Elaine A. / Family-based association analysis of 42 hereditary prostate cancer families identifies the Apolipoprotein L3 region on chromosome 22q12 as a risk locus. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 19. pp. 3852-3862.
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abstract = "Multiple genome-wide scans for hereditary prostate cancer (HPC) have identified susceptibility loci on nearly every chromosome. However, few results have been replicated with statistical significance. One exception is chromosome 22q, for which five independent linkage studies yielded strong evidence for a susceptibility locus in HPC families. Previously, we refined this region to a 2.53 Mb interval, using recombination mapping in 42 linked pedigrees. We now refine this locus to a 15 kb interval, spanning Apolipoprotein L3 (APOL3), using family-based association analyses of 150 total prostate cancer (PC) cases from two independent family collections with 506 unrelated population controls. Analysis of the two independent sets of PC cases highlighted single nucleotide polymorphisms (SNPs) within the APOL3 locus showing the strongest associations with HPC risk, with the most robust results observed when all 150 cases were combined. Analysis of 15 tagSNPs across the 5′ end of the locus identified six SNPs with P-values ≤2 × 10-4. The two independent sets of HPC cases highlight the same 15 kb interval at the 5′ end of the APOL3 gene and provide strong evidence that SNPs within this 15 kb interval, or in strong linkage disequilibrium with it, contribute to HPC risk. Further analyses of this locus in an independent population-based, case-control study revealed an association between an SNP within the APOL3 locus and PC risk, which was not confirmed in the Cancer Genetic Markers of Susceptibility data set. This study further characterizes the 22q locus in HPC risk and suggests that the role of this region in sporadic PC warrants additional studies. Published by Oxford University Press 2010.",
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AU - Deutsch, Kerry

AU - Williams, Gabrielle

AU - Tillmans, Lori S.

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