Meta-analysis of genome-wide association studies identifies ancestry-specific associations underlying circulating total tau levels

Chloé Sarnowski(University of Washington), Mohsen Ghanbari(Mashhad University of Medical Sciences), Joshua C. Bis(University of Washington), Mark W. Logue(Boston University), Myriam Fornage(University of Washington), Aniket Mishra(Université de Bordeaux), Shahzad Ahmad(Leiden University), Alexa Beiser(Boston University), Eric Boerwinkle(University of Washington), Vincent Bouteloup(Université de Bordeaux), Vincent Chouraki(University of Washington), L. Adrienne Cupples(Boston University), Vincent Damotte(University of Washington), Charles DeCarli(University of Washington), Anita L. DeStefano(Boston University), Luc Djoussé(Harvard University), Alison E. Fohner(University of Washington), Carol E. Franz(University of Washington), Tiffany F. Kautz(University of Washington), Jean‐Charles Lambert(University of Washington), Michael J. Lyons(Boston University), Thomas H. Mosley(University of Washington), Kenneth J. Mukamal(Harvard University), Matthew P. Pase(Harvard University), Eliana C. Portilla Fernandez(University of Washington), Robert A. Rissman(University of Washington), Claudia L. Satizábal(Boston University), Ramachandran S. Vasan(Boston University), Amber Yaqub(University of Washington), Stéphanie Debette(Université de Bordeaux), Carole Dufouil(University of Washington), Lenore J. Launer(University of Washington), William S. Kremen(University of Washington), W.T. Longstreth(University of Washington), M. Arfan Ikram(Erasmus MC), Sudha Seshadri(Boston University)
Communications Biology
April 8, 2022
10.1038/s42003-022-03287-y
Cited by 38Open Access
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Abstract

Abstract 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 ( F 5, 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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