Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis

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Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis. / Galatà, Gabriella; García-Montero, Andrés C.; Kristensen, Thomas; Dawoud, Ahmed A.Z.; Muñoz-González, Javier I.; Meggendorfer, Manja; Guglielmelli, Paola; Hoade, Yvette; Alvarez-Twose, Ivan; Gieger, Christian; Strauch, Konstantin; Ferrucci, Luigi; Tanaka, Toshiko; Bandinelli, Stefania; Schnurr, Theresia M.; Haferlach, Torsten; Broesby-Olsen, Sigurd; Vestergaard, Hanne; Møller, Michael Boe; Bindslev-Jensen, Carsten; Vannucchi, Alessandro M.; Orfao, Alberto; Radia, Deepti; Reiter, Andreas; Chase, Andrew J.; Cross, Nicholas C.P.; Tapper, William J.

In: American Journal of Human Genetics, Vol. 108, No. 2, 2021, p. 284-294.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Galatà, G, García-Montero, AC, Kristensen, T, Dawoud, AAZ, Muñoz-González, JI, Meggendorfer, M, Guglielmelli, P, Hoade, Y, Alvarez-Twose, I, Gieger, C, Strauch, K, Ferrucci, L, Tanaka, T, Bandinelli, S, Schnurr, TM, Haferlach, T, Broesby-Olsen, S, Vestergaard, H, Møller, MB, Bindslev-Jensen, C, Vannucchi, AM, Orfao, A, Radia, D, Reiter, A, Chase, AJ, Cross, NCP & Tapper, WJ 2021, 'Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis', American Journal of Human Genetics, vol. 108, no. 2, pp. 284-294. https://doi.org/10.1016/j.ajhg.2020.12.007

APA

Galatà, G., García-Montero, A. C., Kristensen, T., Dawoud, A. A. Z., Muñoz-González, J. I., Meggendorfer, M., Guglielmelli, P., Hoade, Y., Alvarez-Twose, I., Gieger, C., Strauch, K., Ferrucci, L., Tanaka, T., Bandinelli, S., Schnurr, T. M., Haferlach, T., Broesby-Olsen, S., Vestergaard, H., Møller, M. B., ... Tapper, W. J. (2021). Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis. American Journal of Human Genetics, 108(2), 284-294. https://doi.org/10.1016/j.ajhg.2020.12.007

Vancouver

Galatà G, García-Montero AC, Kristensen T, Dawoud AAZ, Muñoz-González JI, Meggendorfer M et al. Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis. American Journal of Human Genetics. 2021;108(2):284-294. https://doi.org/10.1016/j.ajhg.2020.12.007

Author

Galatà, Gabriella ; García-Montero, Andrés C. ; Kristensen, Thomas ; Dawoud, Ahmed A.Z. ; Muñoz-González, Javier I. ; Meggendorfer, Manja ; Guglielmelli, Paola ; Hoade, Yvette ; Alvarez-Twose, Ivan ; Gieger, Christian ; Strauch, Konstantin ; Ferrucci, Luigi ; Tanaka, Toshiko ; Bandinelli, Stefania ; Schnurr, Theresia M. ; Haferlach, Torsten ; Broesby-Olsen, Sigurd ; Vestergaard, Hanne ; Møller, Michael Boe ; Bindslev-Jensen, Carsten ; Vannucchi, Alessandro M. ; Orfao, Alberto ; Radia, Deepti ; Reiter, Andreas ; Chase, Andrew J. ; Cross, Nicholas C.P. ; Tapper, William J. / Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis. In: American Journal of Human Genetics. 2021 ; Vol. 108, No. 2. pp. 284-294.

Bibtex

@article{32f0e59882c84378bf143f3f825d3f2d,
title = "Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis",
abstract = "Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10−15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10−12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10−9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10−14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10−11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (β)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10−8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.",
keywords = "CEBPA, D816V, KIT, mastocytosis, myeloid cancer, TBL1XR1, TERT",
author = "Gabriella Galat{\`a} and Garc{\'i}a-Montero, {Andr{\'e}s C.} and Thomas Kristensen and Dawoud, {Ahmed A.Z.} and Mu{\~n}oz-Gonz{\'a}lez, {Javier I.} and Manja Meggendorfer and Paola Guglielmelli and Yvette Hoade and Ivan Alvarez-Twose and Christian Gieger and Konstantin Strauch and Luigi Ferrucci and Toshiko Tanaka and Stefania Bandinelli and Schnurr, {Theresia M.} and Torsten Haferlach and Sigurd Broesby-Olsen and Hanne Vestergaard and M{\o}ller, {Michael Boe} and Carsten Bindslev-Jensen and Vannucchi, {Alessandro M.} and Alberto Orfao and Deepti Radia and Andreas Reiter and Chase, {Andrew J.} and Cross, {Nicholas C.P.} and Tapper, {William J.}",
year = "2021",
doi = "10.1016/j.ajhg.2020.12.007",
language = "English",
volume = "108",
pages = "284--294",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

RIS

TY - JOUR

T1 - Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis

AU - Galatà, Gabriella

AU - García-Montero, Andrés C.

AU - Kristensen, Thomas

AU - Dawoud, Ahmed A.Z.

AU - Muñoz-González, Javier I.

AU - Meggendorfer, Manja

AU - Guglielmelli, Paola

AU - Hoade, Yvette

AU - Alvarez-Twose, Ivan

AU - Gieger, Christian

AU - Strauch, Konstantin

AU - Ferrucci, Luigi

AU - Tanaka, Toshiko

AU - Bandinelli, Stefania

AU - Schnurr, Theresia M.

AU - Haferlach, Torsten

AU - Broesby-Olsen, Sigurd

AU - Vestergaard, Hanne

AU - Møller, Michael Boe

AU - Bindslev-Jensen, Carsten

AU - Vannucchi, Alessandro M.

AU - Orfao, Alberto

AU - Radia, Deepti

AU - Reiter, Andreas

AU - Chase, Andrew J.

AU - Cross, Nicholas C.P.

AU - Tapper, William J.

PY - 2021

Y1 - 2021

N2 - Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10−15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10−12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10−9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10−14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10−11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (β)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10−8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.

AB - Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10−15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10−12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10−9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10−14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10−11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (β)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10−8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation.

KW - CEBPA

KW - D816V

KW - KIT

KW - mastocytosis

KW - myeloid cancer

KW - TBL1XR1

KW - TERT

U2 - 10.1016/j.ajhg.2020.12.007

DO - 10.1016/j.ajhg.2020.12.007

M3 - Journal article

C2 - 33421400

AN - SCOPUS:85099678562

VL - 108

SP - 284

EP - 294

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -

ID: 260033069