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

Chloé Sarnowski; Mohsen Ghanbari; Joshua C. Bis; Mark Logue; Myriam Fornage; Aniket Mishra; Shahzad Ahmad; Alexa S. Beiser; Eric Boerwinkle; Vincent Bouteloup; Vincent Chouraki; L. Adrienne Cupples; Vincent Damotte; Charles S. DeCarli; Anita L. DeStefano; Luc Djoussé; Alison E. Fohner; Carol E. Franz; Tiffany F. Kautz; Jean Charles Lambert; Michael J. Lyons; Thomas H. Mosley; Kenneth J. Mukamal; Matthew P. Pase; Eliana C. Portilla Fernandez; Robert A. Rissman; Claudia L. Satizabal; Ramachandran S. Vasan; Amber Yaqub; Stephanie Debette; Carole Dufouil; Lenore J. Launer; William S. Kremen; William T. Longstreth; M. Arfan Ikram; Sudha Seshadri

doi:10.1038/s42003-022-03287-y

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

Chloé Sarnowski, Mohsen Ghanbari, Joshua C. Bis, Mark Logue, Myriam Fornage, Aniket Mishra, Shahzad Ahmad, Alexa S. Beiser, Eric Boerwinkle, Vincent Bouteloup, Vincent Chouraki, L. Adrienne Cupples, Vincent Damotte, Charles S. DeCarli, Anita L. DeStefano, Luc Djoussé, Alison E. Fohner, Carol E. Franz, Tiffany F. Kautz, Jean Charles LambertMichael J. Lyons, Thomas H. Mosley, Kenneth J. Mukamal, Matthew P. Pase, Eliana C. Portilla Fernandez, Robert A. Rissman, Claudia L. Satizabal, Ramachandran S. Vasan, Amber Yaqub, Stephanie Debette, Carole Dufouil, Lenore J. Launer, William S. Kremen, William T. Longstreth, M. Arfan Ikram, Sudha Seshadri

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18 Scopus citations

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 (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.

Original language	English (US)
Article number	336
Journal	Communications Biology
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s42003-022-03287-y
State	Published - Dec 2022

ASJC Scopus subject areas

Medicine (miscellaneous)
General Biochemistry, Genetics and Molecular Biology
General Agricultural and Biological Sciences

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10.1038/s42003-022-03287-y

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Sarnowski, C., Ghanbari, M., Bis, J. C., Logue, M., Fornage, M., Mishra, A., Ahmad, S., Beiser, A. S., Boerwinkle, E., Bouteloup, V., Chouraki, V., Cupples, L. A., Damotte, V., DeCarli, C. S., DeStefano, A. L., Djoussé, L., Fohner, A. E., Franz, C. E., Kautz, T. F., ... Seshadri, S. (2022). Meta-analysis of genome-wide association studies identifies ancestry-specific associations underlying circulating total tau levels. Communications Biology, 5(1), Article 336. https://doi.org/10.1038/s42003-022-03287-y

Sarnowski, C, Ghanbari, M, Bis, JC, Logue, M, Fornage, M, Mishra, A, Ahmad, S, Beiser, AS, Boerwinkle, E, Bouteloup, V, Chouraki, V, Cupples, LA, Damotte, V, DeCarli, CS, DeStefano, AL, Djoussé, L, Fohner, AE, Franz, CE, Kautz, TF, Lambert, JC, Lyons, MJ, Mosley, TH, Mukamal, KJ, Pase, MP, Portilla Fernandez, EC, Rissman, RA, Satizabal, CL , Vasan, RS, Yaqub, A, Debette, S, Dufouil, C, Launer, LJ, Kremen, WS, Longstreth, WT, Ikram, MA & Seshadri, S 2022, 'Meta-analysis of genome-wide association studies identifies ancestry-specific associations underlying circulating total tau levels', Communications Biology, vol. 5, no. 1, 336. https://doi.org/10.1038/s42003-022-03287-y

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

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{\textquoteright}s, and Parkinson{\textquoteright}s (F5, MAP1B, and BCAS3), with Alzheimer{\textquoteright}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.",

author = "Chlo{\'e} Sarnowski and Mohsen Ghanbari and Bis, {Joshua C.} and Mark Logue and Myriam Fornage and Aniket Mishra and Shahzad Ahmad and Beiser, {Alexa S.} and Eric Boerwinkle and Vincent Bouteloup and Vincent Chouraki and Cupples, {L. Adrienne} and Vincent Damotte and DeCarli, {Charles S.} and DeStefano, {Anita L.} and Luc Djouss{\'e} and Fohner, {Alison E.} and Franz, {Carol E.} and Kautz, {Tiffany F.} and Lambert, {Jean Charles} and Lyons, {Michael J.} and Mosley, {Thomas H.} and Mukamal, {Kenneth J.} and Pase, {Matthew P.} and {Portilla Fernandez}, {Eliana C.} and Rissman, {Robert A.} and Satizabal, {Claudia L.} and Vasan, {Ramachandran S.} and Amber Yaqub and Stephanie Debette and Carole Dufouil and Launer, {Lenore J.} and Kremen, {William S.} and Longstreth, {William T.} and Ikram, {M. Arfan} and Sudha Seshadri",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s42003-022-03287-y",

language = "English (US)",

volume = "5",

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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

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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JO - Communications Biology

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

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