TY - JOUR
T1 - Investigating the genetic relationship between Alzheimer’s disease and cancer using GWAS summary statistics
AU - Feng, Yen Chen Anne
AU - Cho, Kelly
AU - IGAP Consortium, Colorectal Transdisciplinary Study (CORECT)
AU - Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study
AU - Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE)
AU - Transdisciplinary Research in Cancer of the Lung (TRICL)
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 - Ahsan, Habib
AU - Whittemore, Alice
AU - Waisfisz, Quinten
AU - Meijers-Heijboer, Hanne
AU - Adank, Muriel
AU - van der Luijt, Rob B.
AU - Uitterlinden, Andre G.
AU - Hofman, Albert
AU - Heinrich, Joachim
AU - Liang, Liming
AU - Driver, Jane
N1 - Funding:
This research was funded by the US Department of Veterans Afairs Merit Award Grant Clinical Science R&D [I01CX000934-
01A1] (PI:Driver). The Genetic Association and Mechanisms in Oncology (GAME-ON) network was supported by the National Institutes
of Health [U19CA148065 (DRIVE), U19CA148107 (CORECT),
U19CA148127 (TRICL), and U19CA148537 (ELLIPSE)].
Publisher Copyright:
© 2017, Springer-Verlag GmbH Germany.
PY - 2017/10/1
Y1 - 2017/10/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85026812087&partnerID=8YFLogxK
U2 - 10.1007/s00439-017-1831-6
DO - 10.1007/s00439-017-1831-6
M3 - Article
C2 - 28780673
AN - SCOPUS:85026812087
SN - 0340-6717
VL - 136
SP - 1341
EP - 1351
JO - Human Genetics
JF - Human Genetics
IS - 10
ER -
