Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics

Yen Chen Anne Feng, Kelly Cho, Sara Lindstrom, Peter Kraft, Jean Cormack, IGAP Consortium, Colorectal Transdisciplinary Study (CORECT), Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), Transdisciplinary Research in Cancer of the Lung (TRICL)

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Growing evidence from both epidemiology and basic science suggest an inverse association between Alzheimer’s disease (AD) and cancer. We examined the genetic relationship between AD and various cancer types using GWAS summary statistics from the IGAP and GAME-ON consortia. Sample size ranged from 9931 to 54,162; SNPs were imputed to the 1000 Genomes European panel. Our results based on cross-trait LD Score regression showed a significant positive genetic correlation between AD and five cancers combined (colon, breast, prostate, ovarian, lung; rg = 0.17, P = 0.04), and specifically with breast cancer (ER-negative and overall; rg = 0.21 and 0.18, P = 0.035 and 0.034) and lung cancer (adenocarcinoma, squamous cell carcinoma and overall; rg = 0.31, 0.38 and 0.30, P = 0.029, 0.016, and 0.006). Estimating the genetic correlation in specific functional categories revealed mixed positive and negative signals, notably stronger at annotations associated with increased enhancer activity. This suggests a role of gene expression regulators in the shared genetic etiology between AD and cancer, and that some shared variants modulate disease risk concordantly while others have effects in opposite directions. Due to power issues, we did not detect cross-phenotype associations at individual SNPs. This genetic overlap is not likely driven by a handful of major loci. Our study is the first to examine the co-heritability of AD and cancer leveraging large-scale GWAS results. The functional categories highlighted in this study need further investigation to illustrate the details of the genetic sharing and to bridge between different levels of associations.

Original languageEnglish
Pages (from-to)1341-1351
Number of pages11
JournalHuman Genetics
Volume136
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017

Cite this

Feng, Y. C. A., Cho, K., Lindstrom, S., Kraft, P., Cormack, J., IGAP Consortium, Colorectal Transdisciplinary Study (CORECT), ... Transdisciplinary Research in Cancer of the Lung (TRICL) (2017). Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics. Human Genetics, 136(10), 1341-1351. https://doi.org/10.1007/s00439-017-1831-6
Feng, Yen Chen Anne ; Cho, Kelly ; Lindstrom, Sara ; Kraft, Peter ; Cormack, Jean ; IGAP Consortium, Colorectal Transdisciplinary Study (CORECT) ; Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) ; Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) ; Transdisciplinary Research in Cancer of the Lung (TRICL). / Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics. In: Human Genetics. 2017 ; Vol. 136, No. 10. pp. 1341-1351.
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abstract = "Growing evidence from both epidemiology and basic science suggest an inverse association between Alzheimer’s disease (AD) and cancer. We examined the genetic relationship between AD and various cancer types using GWAS summary statistics from the IGAP and GAME-ON consortia. Sample size ranged from 9931 to 54,162; SNPs were imputed to the 1000 Genomes European panel. Our results based on cross-trait LD Score regression showed a significant positive genetic correlation between AD and five cancers combined (colon, breast, prostate, ovarian, lung; rg = 0.17, P = 0.04), and specifically with breast cancer (ER-negative and overall; rg = 0.21 and 0.18, P = 0.035 and 0.034) and lung cancer (adenocarcinoma, squamous cell carcinoma and overall; rg = 0.31, 0.38 and 0.30, P = 0.029, 0.016, and 0.006). Estimating the genetic correlation in specific functional categories revealed mixed positive and negative signals, notably stronger at annotations associated with increased enhancer activity. This suggests a role of gene expression regulators in the shared genetic etiology between AD and cancer, and that some shared variants modulate disease risk concordantly while others have effects in opposite directions. Due to power issues, we did not detect cross-phenotype associations at individual SNPs. This genetic overlap is not likely driven by a handful of major loci. Our study is the first to examine the co-heritability of AD and cancer leveraging large-scale GWAS results. The functional categories highlighted in this study need further investigation to illustrate the details of the genetic sharing and to bridge between different levels of associations.",
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Feng, YCA, Cho, K, Lindstrom, S, Kraft, P, Cormack, J, IGAP Consortium, Colorectal Transdisciplinary Study (CORECT), Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) & Transdisciplinary Research in Cancer of the Lung (TRICL) 2017, 'Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics' Human Genetics, vol. 136, no. 10, pp. 1341-1351. https://doi.org/10.1007/s00439-017-1831-6

Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics. / Feng, Yen Chen Anne; Cho, Kelly; Lindstrom, Sara; Kraft, Peter; Cormack, Jean; IGAP Consortium, Colorectal Transdisciplinary Study (CORECT); Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE); Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE); Transdisciplinary Research in Cancer of the Lung (TRICL).

In: Human Genetics, Vol. 136, No. 10, 01.10.2017, p. 1341-1351.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Feng, Yen Chen Anne

AU - Cho, Kelly

AU - Lindstrom, Sara

AU - Kraft, Peter

AU - Cormack, Jean

AU - Blalock, Kendra

AU - Campbell, Peter T.

AU - Casey, Graham

AU - Conti, David V.

AU - Edlund, Christopher K.

AU - Figueiredo, Jane

AU - James Gauderman, W.

AU - Gong, Jian

AU - Green, Roger C.

AU - Gruber, Stephen B.

AU - Harju, John F.

AU - Harrison, Tabitha A.

AU - Jacobs, Eric J.

AU - Jenkins, Mark A.

AU - Jiao, Shuo

AU - Li, Li

AU - Lin, Yi

AU - Manion, Frank J.

AU - Moreno, Victor

AU - Mukherjee, Bhramar

AU - Peters, Ulrike

AU - Raskin, Leon

AU - Schumacher, Fredrick R.

AU - Seminara, Daniela

AU - Severi, Gianluca

AU - Stenzel, Stephanie L.

AU - Thomas, Duncan C.

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Makalic, Enes

AU - Schmidt, Daniel F.

AU - Fletcher, Olivia

AU - Peto, Julian

AU - Gibson, Lorna

AU - dos Santos Silva, Isabel

AU - Hunter, David J.

AU - Lindström, Sara

AU - Kraft, Peter

AU - Ahsan, Habib

AU - Whittemore, Alice

AU - Waisfisz, Quinten

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AU - Adank, Muriel

AU - van der Luijt, Rob B.

AU - Uitterlinden, Andre G.

AU - IGAP Consortium, Colorectal Transdisciplinary Study (CORECT)

AU - Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE)

AU - Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE)

AU - Transdisciplinary Research in Cancer of the Lung (TRICL)

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N2 - Growing evidence from both epidemiology and basic science suggest an inverse association between Alzheimer’s disease (AD) and cancer. We examined the genetic relationship between AD and various cancer types using GWAS summary statistics from the IGAP and GAME-ON consortia. Sample size ranged from 9931 to 54,162; SNPs were imputed to the 1000 Genomes European panel. Our results based on cross-trait LD Score regression showed a significant positive genetic correlation between AD and five cancers combined (colon, breast, prostate, ovarian, lung; rg = 0.17, P = 0.04), and specifically with breast cancer (ER-negative and overall; rg = 0.21 and 0.18, P = 0.035 and 0.034) and lung cancer (adenocarcinoma, squamous cell carcinoma and overall; rg = 0.31, 0.38 and 0.30, P = 0.029, 0.016, and 0.006). Estimating the genetic correlation in specific functional categories revealed mixed positive and negative signals, notably stronger at annotations associated with increased enhancer activity. This suggests a role of gene expression regulators in the shared genetic etiology between AD and cancer, and that some shared variants modulate disease risk concordantly while others have effects in opposite directions. Due to power issues, we did not detect cross-phenotype associations at individual SNPs. This genetic overlap is not likely driven by a handful of major loci. Our study is the first to examine the co-heritability of AD and cancer leveraging large-scale GWAS results. The functional categories highlighted in this study need further investigation to illustrate the details of the genetic sharing and to bridge between different levels of associations.

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Feng YCA, Cho K, Lindstrom S, Kraft P, Cormack J, IGAP Consortium, Colorectal Transdisciplinary Study (CORECT) et al. Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics. Human Genetics. 2017 Oct 1;136(10):1341-1351. https://doi.org/10.1007/s00439-017-1831-6