A genome-wide association study of plasma phosphorylated tau181

TY - JOUR

T1 - A genome-wide association study of plasma phosphorylated tau181

AU - Lord, Jodie

AU - Zettergren, Anna

AU - Ashton, Nick

AU - Karkari, Thomas

AU - Benedet, Andrea

AU - Simren, Joel

AU - Hye, Abdul

AU - Aarsland, Dag

AU - Zetterberg, Henrik

AU - Blennow, Kaj

AU - Proitsi, Petra

N1 - Funding Information: PP is an Alzheimer's Research UK Senior Research Fellow (#ARUK-SRF2016A-3). JL is funded by the van Geest Endowment Fund. TKK holds a Brightfocus fellowship and is further supported by the Swedish Alzheimer Foundation (Alzheimerfonden), the Swedish Brain Foundation (Hj?rnfonden), the Swedish Dementia Foundation (Demensf?rbundet), the Swedish Parkinson Foundation (Parkinsonfonden), Gamla Tj?narinnor, the Aina (Ann) Wallstr?ms and Mary-Ann Sj?bloms Foundation, the Gun and Bertil Stohnes Foundation, and the Anna Lisa and Brother Bj?rnsson's Foundation. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hj?rnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), and the National Institute of Health (NIH), USA, (grant #1R01AG068398-01). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen f?r Gamla Tj?narinnor, Hj?rnfonden, Sweden (#FO2019-0228), the European Union's Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. This paper represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Funding Information: PP is an Alzheimer's Research UK Senior Research Fellow (#ARUK-SRF2016A-3) . JL is funded by the van Geest Endowment Fund . TKK holds a Brightfocus fellowship and is further supported by the Swedish Alzheimer Foundation (Alzheimerfonden) , the Swedish Brain Foundation (Hjärnfonden) , the Swedish Dementia Foundation (Demensförbundet) , the Swedish Parkinson Foundation (Parkinsonfonden) , Gamla Tjänarinnor, the Aina (Ann) Wallströms and Mary-Ann Sjöbloms Foundation , the Gun and Bertil Stohnes Foundation , and the Anna Lisa and Brother Björnsson's Foundation . KB is supported by the Swedish Research Council ( #2017-00915 ), the Alzheimer Drug Discovery Foundation (ADDF), USA ( #RDAPB-201809-2016615 ), the Swedish Alzheimer Foundation ( #AF-742881 ), Hjärnfonden, Sweden ( #FO2017-0243 ), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement ( #ALFGBG-715986 ), the European Union Joint Program for Neurodegenerative Disorders ( JPND2019-466-236 ), and the National Institute of Health (NIH), USA , (grant #1R01AG068398-01 ). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council ( #2018-02532 ), the European Research Council ( #681712 ), Swedish State Support for Clinical Research ( #ALFGBG-720931 ), the Alzheimer Drug Discovery Foundation (ADDF), USA ( #201809-2016862 ), the AD Strategic Fund and the Alzheimer's Association ( #ADSF-21-831376-C , #ADSF-21-831381-C , and #ADSF-21-831377-C ), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden ( #FO2019-0228 ), the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL . This paper represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Publisher Copyright: © 2021 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/10

Y1 - 2021/10

N2 - Plasma phosphorylated tau at threonine-181 (P-tau181) demonstrates promise as an accessible blood-based biomarker specific to Alzheimer's Disease (AD), with levels recently demonstrating high predictive accuracy for AD-relevant pathology. The genetic underpinnings of P-tau181 levels, however, remain elusive. This study presents the first genome-wide association study of plasma P-tau181 in a total sample of 1153 participants from 2 independent cohorts. No loci, other than those within the APOE genomic region (lead variant = rs429358, beta = 0.32, p =8.44 × 10 −25) demonstrated association with P-tau181 at genome-wide significance (p < 5 × 10 −08), though rs60872856 on chromosome 2 came close (beta = -0.28, p = 3.23 × 10 −07, nearest gene=CYTIP). As the APOE ε4 allele is already a well-established genetic variant associated with AD, this study found no evidence of novel genetic associations relevant to plasma P-tau181, though presents rs60872856 on chromosome 2 as a candidate locus to be further evaluated in future larger size GWAS.

AB - Plasma phosphorylated tau at threonine-181 (P-tau181) demonstrates promise as an accessible blood-based biomarker specific to Alzheimer's Disease (AD), with levels recently demonstrating high predictive accuracy for AD-relevant pathology. The genetic underpinnings of P-tau181 levels, however, remain elusive. This study presents the first genome-wide association study of plasma P-tau181 in a total sample of 1153 participants from 2 independent cohorts. No loci, other than those within the APOE genomic region (lead variant = rs429358, beta = 0.32, p =8.44 × 10 −25) demonstrated association with P-tau181 at genome-wide significance (p < 5 × 10 −08), though rs60872856 on chromosome 2 came close (beta = -0.28, p = 3.23 × 10 −07, nearest gene=CYTIP). As the APOE ε4 allele is already a well-established genetic variant associated with AD, this study found no evidence of novel genetic associations relevant to plasma P-tau181, though presents rs60872856 on chromosome 2 as a candidate locus to be further evaluated in future larger size GWAS.

KW - Plasma biomarkers

KW - P-tau181

KW - GWAS

UR - http://www.scopus.com/inward/record.url?scp=85107790380&partnerID=8YFLogxK

U2 - S0197-4580(21)00134-2

DO - S0197-4580(21)00134-2

M3 - Article

SN - 0197-4580

VL - 106

SP - 304.e1-304.e3

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -