Meta-analysis of genome-wide association studies identifies ancestry-specific associations underlying circulating total tau levels
Chloe Sarnowski
(1)
,
Mohsen Ghanbari
(2, 3)
,
Joshua C. Bis
(4)
,
Mark Logue
(5, 6)
,
Myriam Fornage
(1)
,
Aniket Mishra
(7)
,
Shahzad Ahmad
(2, 8)
,
Alexa S. Beiser
(9, 6)
,
Eric Boerwinkle
(1)
,
Vincent Bouteloup
(7, 10, 11, 12)
,
Vincent Chouraki
(13, 14, 15)
,
L. Adrienne Cupples
(9)
,
Vincent Damotte
(13, 14, 15)
,
Charles S. Decarli
(16)
,
Anita L. Destefano
(9)
,
Luc Djousse
(17)
,
Alison E. Fohner
(4)
,
Carol E. Franz
(18)
,
Tiffany F. Kautz
(19)
,
Jean-Charles Lambert
(13, 14, 15)
,
Michael J. Lyons
(9)
,
Thomas H. Mosley
(20)
,
Kenneth J. Mukamal
(17)
,
Matthew P. Pase
(21, 22)
,
Eliana C. Portilla Fernandez
(2)
,
Robert A. Rissman
(18)
,
Claudia L. Satizabal
(9, 6, 19)
,
Ramachandran S. Vasan
(9, 6)
,
Amber Yaqub
(2)
,
Stephanie Debette
(7, 12)
,
Carole Dufouil
(12)
,
Lenore J. Launer
(23)
,
William S. Kremen
(18)
,
William T. Longstreth
(4)
,
M. Arfan Ikram
(2)
,
Sudha Seshadri
(9, 6, 19)
1
UTHealth -
The University of Texas Health Science Center at Houston
2 Erasmus MC - Erasmus University Medical Center [Rotterdam]
3 Mashhad University of Medical Sciences
4 University of Washington [Seattle]
5 VA Boston Healthcare System
6 BUSM - Boston University School of Medicine
7 BPH - Bordeaux population health
8 Universiteit Leiden = Leiden University
9 BU - Boston University [Boston]
10 CIC Bordeaux
11 ISPED - Institut de Santé Publique, d'Epidémiologie et de Développement
12 CHU Bordeaux
13 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
14 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
15 Excellence Laboratory LabEx DISTALZ
16 UC Davis - University of California [Davis]
17 HMS - Harvard Medical School [Boston]
18 UC San Diego - University of California [San Diego]
19 UTSA - The University of Texas at San Antonio
20 UMMC - University of Mississippi Medical Center
21 Monash University [Melbourne]
22 Harvard T.H. Chan School of Public Health
23 NIA - National Institute on Aging [Bethesda, USA]
2 Erasmus MC - Erasmus University Medical Center [Rotterdam]
3 Mashhad University of Medical Sciences
4 University of Washington [Seattle]
5 VA Boston Healthcare System
6 BUSM - Boston University School of Medicine
7 BPH - Bordeaux population health
8 Universiteit Leiden = Leiden University
9 BU - Boston University [Boston]
10 CIC Bordeaux
11 ISPED - Institut de Santé Publique, d'Epidémiologie et de Développement
12 CHU Bordeaux
13 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
14 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
15 Excellence Laboratory LabEx DISTALZ
16 UC Davis - University of California [Davis]
17 HMS - Harvard Medical School [Boston]
18 UC San Diego - University of California [San Diego]
19 UTSA - The University of Texas at San Antonio
20 UMMC - University of Mississippi Medical Center
21 Monash University [Melbourne]
22 Harvard T.H. Chan School of Public Health
23 NIA - National Institute on Aging [Bethesda, USA]
Résumé
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.
Domaines
Santé publique et épidémiologie
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