TY - JOUR
T1 - Meta-analysis of genome-wide association studies identifies ancestry-specific associations underlying circulating total tau levels
AU - Sarnowski, Chloé
AU - Ghanbari, Mohsen
AU - Bis, Joshua C.
AU - Logue, Mark
AU - Fornage, Myriam
AU - Mishra, Aniket
AU - Ahmad, Shahzad
AU - Beiser, Alexa S.
AU - Boerwinkle, Eric
AU - Bouteloup, Vincent
AU - Chouraki, Vincent
AU - Cupples, L. Adrienne
AU - Damotte, Vincent
AU - DeCarli, Charles S.
AU - DeStefano, Anita L.
AU - Djoussé, Luc
AU - Fohner, Alison E.
AU - Franz, Carol E.
AU - Kautz, Tiffany F.
AU - Lambert, Jean Charles
AU - Lyons, Michael J.
AU - Mosley, Thomas H.
AU - Mukamal, Kenneth J.
AU - Pase, Matthew P.
AU - Portilla Fernandez, Eliana C.
AU - Rissman, Robert A.
AU - Satizabal, Claudia L.
AU - Vasan, Ramachandran S.
AU - Yaqub, Amber
AU - Debette, Stephanie
AU - Dufouil, Carole
AU - Launer, Lenore J.
AU - Kremen, William S.
AU - Longstreth, William T.
AU - Ikram, M. Arfan
AU - Seshadri, Sudha
N1 - Funding Information:
We thank all the participating cohorts from the CHARGE consortium and ADNI participants for contributing to this study. Detailed study-specific acknowledgements are provided in the Supplementary Notes 11 and 12.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10−8. We additionally detected 14 novel loci at P < 5 × 10−7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer’s, and Parkinson’s (F5, MAP1B, and BCAS3), with Alzheimer’s pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.
AB - Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10−8. We additionally detected 14 novel loci at P < 5 × 10−7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer’s, and Parkinson’s (F5, MAP1B, and BCAS3), with Alzheimer’s pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.
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U2 - 10.1038/s42003-022-03287-y
DO - 10.1038/s42003-022-03287-y
M3 - Article
C2 - 35396452
AN - SCOPUS:85127861965
SN - 2399-3642
VL - 5
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 336
ER -