Yassine Zouaghi

All Publications

• Publisher Correction: Understanding the genetic complexity of puberty timing across the allele frequency spectrum. Nature genetics Kentistou, K. A., Kaisinger, L. R., Stankovic, S., Vaudel, M., Mendes de Oliveira, E., Messina, A., Walters, R. G., Liu, X., Busch, A. S., Helgason, H., Thompson, D. J., Santoni, F., Petricek, K. M., Zouaghi, Y., Huang-Doran, I., Gudbjartsson, D. F., Bratland, E., Lin, K., Gardner, E. J., Zhao, Y., Jia, R. Y., Terao, C., Riggan, M. J., Bolla, M. K., Yazdanpanah, M., Yazdanpanah, N., Bradfield, J. P., Broer, L., Campbell, A., Chasman, D. I., Cousminer, D. L., Franceschini, N., Franke, L. H., Girotto, G., He, C., Järvelin, M. R., Joshi, P. K., Kamatani, Y., Karlsson, R., Luan, J., Lunetta, K. L., Mägi, R., Mangino, M., Medland, S. E., Meisinger, C., Noordam, R., Nutile, T., Concas, M. P., Polašek, O., Porcu, E., Ring, S. M., Sala, C., Smith, A. V., Tanaka, T., van der Most, P. J., Vitart, V., Wang, C. A., Willemsen, G., Zygmunt, M., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Auer, P. L., Barnes, C. L., Beckmann, M. W., Berrington de Gonzalez, A., Bogdanova, N. V., Bojesen, S. E., Brenner, H., Buring, J. E., Canzian, F., Chang-Claude, J., Couch, F. J., Cox, A., Crisponi, L., Czene, K., Daly, M. B., Demerath, E. W., Dennis, J., Devilee, P., De Vivo, I., Dörk, T., Dunning, A. M., Dwek, M., Eriksson, J. G., Fasching, P. A., Fernandez-Rhodes, L., Ferreli, L., Fletcher, O., Gago-Dominguez, M., García-Closas, M., García-Sáenz, J. A., González-Neira, A., Grallert, H., Guénel, P., Haiman, C. A., Hall, P., Hamann, U., Hakonarson, H., Hart, R. J., Hickey, M., Hooning, M. J., Hoppe, R., Hopper, J. L., Hottenga, J. J., Hu, F. B., Huebner, H., Hunter, D. J., Jernström, H., John, E. M., Karasik, D., Khusnutdinova, E. K., Kristensen, V. N., Lacey, J. V., Lambrechts, D., Launer, L. J., Lind, P. A., Lindblom, A., Magnusson, P. K., Mannermaa, A., McCarthy, M. I., Meitinger, T., Menni, C., Michailidou, K., Millwood, I. Y., Milne, R. L., Montgomery, G. W., Nevanlinna, H., Nolte, I. M., Nyholt, D. R., Obi, N., O'Brien, K. M., Offit, K., Oldehinkel, A. J., Ostrowski, S. R., Palotie, A., Pedersen, O. B., Peters, A., Pianigiani, G., Plaseska-Karanfilska, D., Pouta, A., Pozarickij, A., Radice, P., Rennert, G., Rosendaal, F. R., Ruggiero, D., Saloustros, E., Sandler, D. P., Schipf, S., Schmidt, C. O., Schmidt, M. K., Small, K., Spedicati, B., Stampfer, M., Stone, J., Tamimi, R. M., Teras, L. R., Tikkanen, E., Turman, C., Vachon, C. M., Wang, Q., Winqvist, R., Wolk, A., Zemel, B. S., Zheng, W., van Dijk, K. W., Alizadeh, B. Z., Bandinelli, S., Boerwinkle, E., Boomsma, D. I., Ciullo, M., Chenevix-Trench, G., Cucca, F., Esko, T., Gieger, C., Grant, S. F., Gudnason, V., Hayward, C., Kolčić, I., Kraft, P., Lawlor, D. A., Martin, N. G., Nøhr, E. A., Pedersen, N. L., Pennell, C. E., Ridker, P. M., Robino, A., Snieder, H., Sovio, U., Spector, T. D., Stöckl, D., Sudlow, C., Timpson, N. J., Toniolo, D., Uitterlinden, A., Ulivi, S., Völzke, H., Wareham, N. J., Widen, E., Wilson, J. F., Pharoah, P. D., Li, L., Easton, D. F., Njølstad, P. R., Sulem, P., Murabito, J. M., Murray, A., Manousaki, D., Juul, A., Erikstrup, C., Stefansson, K., Horikoshi, M., Chen, Z., Farooqi, I. S., Pitteloud, N., Johansson, S., Day, F. R., Perry, J. R., Ong, K. K. 2024

  View details for DOI 10.1038/s41588-024-01857-w

  View details for PubMedID 38982295

• Understanding the genetic complexity of puberty timing across the allele frequency spectrum. Nature genetics Kentistou, K. A., Kaisinger, L. R., Stankovic, S., Vaudel, M., Mendes de Oliveira, E., Messina, A., Walters, R. G., Liu, X., Busch, A. S., Helgason, H., Thompson, D. J., Santoni, F., Petricek, K. M., Zouaghi, Y., Huang-Doran, I., Gudbjartsson, D. F., Bratland, E., Lin, K., Gardner, E. J., Zhao, Y., Jia, R. Y., Terao, C., Riggan, M. J., Bolla, M. K., Yazdanpanah, M., Yazdanpanah, N., Bradfield, J. P., Broer, L., Campbell, A., Chasman, D. I., Cousminer, D. L., Franceschini, N., Franke, L. H., Girotto, G., He, C., Järvelin, M. R., Joshi, P. K., Kamatani, Y., Karlsson, R., Luan, J., Lunetta, K. L., Mägi, R., Mangino, M., Medland, S. E., Meisinger, C., Noordam, R., Nutile, T., Concas, M. P., Polašek, O., Porcu, E., Ring, S. M., Sala, C., Smith, A. V., Tanaka, T., van der Most, P. J., Vitart, V., Wang, C. A., Willemsen, G., Zygmunt, M., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Auer, P. L., Barnes, C. L., Beckmann, M. W., Berrington de Gonzalez, A., Bogdanova, N. V., Bojesen, S. E., Brenner, H., Buring, J. E., Canzian, F., Chang-Claude, J., Couch, F. J., Cox, A., Crisponi, L., Czene, K., Daly, M. B., Demerath, E. W., Dennis, J., Devilee, P., De Vivo, I., Dörk, T., Dunning, A. M., Dwek, M., Eriksson, J. G., Fasching, P. A., Fernandez-Rhodes, L., Ferreli, L., Fletcher, O., Gago-Dominguez, M., García-Closas, M., García-Sáenz, J. A., González-Neira, A., Grallert, H., Guénel, P., Haiman, C. A., Hall, P., Hamann, U., Hakonarson, H., Hart, R. J., Hickey, M., Hooning, M. J., Hoppe, R., Hopper, J. L., Hottenga, J. J., Hu, F. B., Huebner, H., Hunter, D. J., Jernström, H., John, E. M., Karasik, D., Khusnutdinova, E. K., Kristensen, V. N., Lacey, J. V., Lambrechts, D., Launer, L. J., Lind, P. A., Lindblom, A., Magnusson, P. K., Mannermaa, A., McCarthy, M. I., Meitinger, T., Menni, C., Michailidou, K., Millwood, I. Y., Milne, R. L., Montgomery, G. W., Nevanlinna, H., Nolte, I. M., Nyholt, D. R., Obi, N., O'Brien, K. M., Offit, K., Oldehinkel, A. J., Ostrowski, S. R., Palotie, A., Pedersen, O. B., Peters, A., Pianigiani, G., Plaseska-Karanfilska, D., Pouta, A., Pozarickij, A., Radice, P., Rennert, G., Rosendaal, F. R., Ruggiero, D., Saloustros, E., Sandler, D. P., Schipf, S., Schmidt, C. O., Schmidt, M. K., Small, K., Spedicati, B., Stampfer, M., Stone, J., Tamimi, R. M., Teras, L. R., Tikkanen, E., Turman, C., Vachon, C. M., Wang, Q., Winqvist, R., Wolk, A., Zemel, B. S., Zheng, W., van Dijk, K. W., Alizadeh, B. Z., Bandinelli, S., Boerwinkle, E., Boomsma, D. I., Ciullo, M., Chenevix-Trench, G., Cucca, F., Esko, T., Gieger, C., Grant, S. F., Gudnason, V., Hayward, C., Kolčić, I., Kraft, P., Lawlor, D. A., Martin, N. G., Nøhr, E. A., Pedersen, N. L., Pennell, C. E., Ridker, P. M., Robino, A., Snieder, H., Sovio, U., Spector, T. D., Stöckl, D., Sudlow, C., Timpson, N. J., Toniolo, D., Uitterlinden, A., Ulivi, S., Völzke, H., Wareham, N. J., Widen, E., Wilson, J. F., Pharoah, P. D., Li, L., Easton, D. F., Njølstad, P. R., Sulem, P., Murabito, J. M., Murray, A., Manousaki, D., Juul, A., Erikstrup, C., Stefansson, K., Horikoshi, M., Chen, Z., Farooqi, I. S., Pitteloud, N., Johansson, S., Day, F. R., Perry, J. R., Ong, K. K. 2024

  Abstract

  Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

  View details for DOI 10.1038/s41588-024-01798-4

  View details for PubMedID 38951643

  View details for PubMedCentralID 6185946

• Understanding the genetic complexity of puberty timing across the allele frequency spectrum. medRxiv : the preprint server for health sciences Kentistou, K. A., Kaisinger, L. R., Stankovic, S., Vaudel, M., de Oliveira, E. M., Messina, A., Walters, R. G., Liu, X., Busch, A. S., Helgason, H., Thompson, D. J., Santon, F., Petricek, K. M., Zouaghi, Y., Huang-Doran, I., Gudbjartsson, D. F., Bratland, E., Lin, K., Gardner, E. J., Zhao, Y., Jia, R., Terao, C., Riggan, M., Bolla, M. K., Yazdanpanah, M., Yazdanpanah, N., Bradfield, J. P., Broer, L., Campbell, A., Chasman, D. I., Cousminer, D. L., Franceschini, N., Franke, L. H., Girotto, G., He, C., Järvelin, M. R., Joshi, P. K., Kamatani, Y., Karlsson, R., Luan, J., Lunetta, K. L., Mägi, R., Mangino, M., Medland, S. E., Meisinger, C., Noordam, R., Nutile, T., Concas, M. P., Polašek, O., Porcu, E., Ring, S. M., Sala, C., Smith, A. V., Tanaka, T., van der Most, P. J., Vitart, V., Wang, C. A., Willemsen, G., Zygmunt, M., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antoniou, A. C., Auer, P. L., Barnes, C. L., Beckmann, M. W., Berrington, A., Bogdanova, N. V., Bojesen, S. E., Brenner, H., Buring, J. E., Canzian, F., Chang-Claude, J., Couch, F. J., Cox, A., Crisponi, L., Czene, K., Daly, M. B., Demerath, E. W., Dennis, J., Devilee, P., Vivo, I. D., Dörk, T., Dunning, A. M., Dwek, M., Eriksson, J. G., Fasching, P. A., Fernandez-Rhodes, L., Ferreli, L., Fletcher, O., Gago-Dominguez, M., García-Closas, M., García-Sáenz, J. A., González-Neira, A., Grallert, H., Guénel, P., Haiman, C. A., Hall, P., Hamann, U., Hakonarson, H., Hart, R. J., Hickey, M., Hooning, M. J., Hoppe, R., Hopper, J. L., Hottenga, J. J., Hu, F. B., Hübner, H., Hunter, D. J., Jernström, H., John, E. M., Karasik, D., Khusnutdinova, E. K., Kristensen, V. N., Lacey, J. V., Lambrechts, D., Launer, L. J., Lind, P. A., Lindblom, A., Magnusson, P. K., Mannermaa, A., McCarthy, M. I., Meitinger, T., Menni, C., Michailidou, K., Millwood, I. Y., Milne, R. L., Montgomery, G. W., Nevanlinna, H., Nolte, I. M., Nyholt, D. R., Obi, N., O'Brien, K. M., Offit, K., Oldehinkel, A. J., Ostrowski, S. R., Palotie, A., Pedersen, O. B., Peters, A., Pianigiani, G., Plaseska-Karanfilska, D., Pouta, A., Pozarickij, A., Radice, P., Rennert, G., Rosendaal, F. R., Ruggiero, D., Saloustros, E., Sandler, D. P., Schipf, S., Schmidt, C. O., Schmidt, M. K., Small, K., Spedicati, B., Stampfer, M., Stone, J., Tamimi, R. M., Teras, L. R., Tikkanen, E., Turman, C., Vachon, C. M., Wang, Q., Winqvist, R., Wolk, A., Zemel, B. S., Zheng, W., van Dijk, K. W., Alizadeh, B. Z., Bandinelli, S., Boerwinkle, E., Boomsma, D. I., Ciullo, M., Chenevix-Trench, G., Cucca, F., Esko, T., Gieger, C., Grant, S. F., Gudnason, V., Hayward, C., Kolčić, I., Kraft, P., Lawlor, D. A., Martin, N. G., Nøhr, E. A., Pedersen, N. L., Pennell, C. E., Ridker, P. M., Robino, A., Snieder, H., Sovio, U., Spector, T. D., Stöckl, D., Sudlow, C., Timpson, N. J., Toniolo, D., Uitterlinden, A., Ulivi, S., Völzke, H., Wareham, N. J., Widen, E., Wilson, J. F., Pharoah, P. D., Li, L., Easton, D. F., Njølstad, P., Sulem, P., Murabito, J. M., Murray, A., Manousaki, D., Juul, A., Erikstrup, C., Stefansson, K., Horikoshi, M., Chen, Z., Farooqi, I. S., Pitteloud, N., Johansson, S., Day, F. R., Perry, J. R., Ong, K. K. 2023

  Abstract

  Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ~11 and ~14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ~220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83, which we demonstrate amplifies signaling of MC3R, a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.

  View details for DOI 10.1101/2023.06.14.23291322

  View details for PubMedID 37503126

  View details for PubMedCentralID PMC10371120