Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred

Jesse Nicholas Cochran; Juliana Acosta-Uribe; Bianca T. Esposito; Lucia Madrigal; David Aguillón; Margarita M. Giraldo; Jared W. Taylor; Joseph Bradley; Brian Fulton-Howard; Shea J. Andrews; Natalia Acosta-Baena; Diana Alzate; Gloria P. Garcia; Francisco Piedrahita; Hugo E. Lopez; Ashlyn G. Anderson; Ivan Rodriguez-Nunez; Kevin Roberts; I. Dominantly; Devin Absher; Richard M. Myers; Gary W. Beecham; Christiane Reitz; Lindsay F. Rizzardi; Maria Victoria Fernandez; Alison M. Goate; Carlos Cruchaga; Alan E. Renton; Francisco Lopera; Kenneth S. Kosik

doi:10.1002/alz.13021

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred

Jesse Nicholas Cochran, Juliana Acosta-Uribe, Bianca T. Esposito, Lucia Madrigal, David Aguillón, Margarita M. Giraldo, Jared W. Taylor, Joseph Bradley, Brian Fulton-Howard, Shea J. Andrews, Natalia Acosta-Baena, Diana Alzate, Gloria P. Garcia, Francisco Piedrahita, Hugo E. Lopez, Ashlyn G. Anderson, Ivan Rodriguez-Nunez, Kevin Roberts, I. Dominantly, Devin AbsherRichard M. Myers, Gary W. Beecham, Christiane Reitz, Lindsay F. Rizzardi, Maria Victoria Fernandez, Alison M. Goate, Carlos Cruchaga, Alan E. Renton, Francisco Lopera, Kenneth S. Kosik

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10⁻⁷ or p<1×10⁻⁵ with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

Original language	English
Pages (from-to)	3835-3847
Number of pages	13
Journal	Alzheimer's and Dementia
Volume	19
Issue number	9
DOIs	https://doi.org/10.1002/alz.13021
State	Published - Sep 2023

Keywords

AAO
ACE
AOO
Alzheimer
CLU
E280A
HS3ST1
HSPG2
LRP1B
PSEN1
SIAH3
TSPAN10
TSPAN14
ZC3H13
age of onset
amyloid
clusterin
heparin sulfate
tetraspanin

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10.1002/alz.13021

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Cochran, J. N., Acosta-Uribe, J., Esposito, B. T., Madrigal, L., Aguillón, D., Giraldo, M. M., Taylor, J. W., Bradley, J., Fulton-Howard, B., Andrews, S. J., Acosta-Baena, N., Alzate, D., Garcia, G. P., Piedrahita, F., Lopez, H. E., Anderson, A. G., Rodriguez-Nunez, I., Roberts, K., Dominantly, I., ... Kosik, K. S. (2023). Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred. Alzheimer's and Dementia, 19(9), 3835-3847. https://doi.org/10.1002/alz.13021

@article{f86911018045499f8abba51876153ba3,

title = "Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred",

abstract = "INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10−7 or p<1×10−5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.",

keywords = "AAO, ACE, AOO, Alzheimer, CLU, E280A, HS3ST1, HSPG2, LRP1B, PSEN1, SIAH3, TSPAN10, TSPAN14, ZC3H13, age of onset, amyloid, clusterin, heparin sulfate, tetraspanin",

author = "Cochran, {Jesse Nicholas} and Juliana Acosta-Uribe and Esposito, {Bianca T.} and Lucia Madrigal and David Aguill{\'o}n and Giraldo, {Margarita M.} and Taylor, {Jared W.} and Joseph Bradley and Brian Fulton-Howard and Andrews, {Shea J.} and Natalia Acosta-Baena and Diana Alzate and Garcia, {Gloria P.} and Francisco Piedrahita and Lopez, {Hugo E.} and Anderson, {Ashlyn G.} and Ivan Rodriguez-Nunez and Kevin Roberts and I. Dominantly and Devin Absher and Myers, {Richard M.} and Beecham, {Gary W.} and Christiane Reitz and Rizzardi, {Lindsay F.} and Fernandez, {Maria Victoria} and Goate, {Alison M.} and Carlos Cruchaga and Renton, {Alan E.} and Francisco Lopera and Kosik, {Kenneth S.}",

note = "Publisher Copyright: {\textcopyright} 2023 Alzheimer's Association.",

year = "2023",

month = sep,

doi = "10.1002/alz.13021",

language = "English",

volume = "19",

pages = "3835--3847",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

number = "9",

}

Cochran, JN, Acosta-Uribe, J, Esposito, BT, Madrigal, L, Aguillón, D, Giraldo, MM, Taylor, JW, Bradley, J, Fulton-Howard, B, Andrews, SJ, Acosta-Baena, N, Alzate, D, Garcia, GP, Piedrahita, F, Lopez, HE, Anderson, AG, Rodriguez-Nunez, I, Roberts, K, Dominantly, I, Absher, D, Myers, RM, Beecham, GW, Reitz, C, Rizzardi, LF, Fernandez, MV, Goate, AM, Cruchaga, C, Renton, AE, Lopera, F & Kosik, KS 2023, 'Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred', Alzheimer's and Dementia, vol. 19, no. 9, pp. 3835-3847. https://doi.org/10.1002/alz.13021

TY - JOUR

T1 - Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred

AU - Cochran, Jesse Nicholas

AU - Acosta-Uribe, Juliana

AU - Esposito, Bianca T.

AU - Madrigal, Lucia

AU - Aguillón, David

AU - Giraldo, Margarita M.

AU - Taylor, Jared W.

AU - Bradley, Joseph

AU - Fulton-Howard, Brian

AU - Andrews, Shea J.

AU - Acosta-Baena, Natalia

AU - Alzate, Diana

AU - Garcia, Gloria P.

AU - Piedrahita, Francisco

AU - Lopez, Hugo E.

AU - Anderson, Ashlyn G.

AU - Rodriguez-Nunez, Ivan

AU - Roberts, Kevin

AU - Dominantly, I.

AU - Absher, Devin

AU - Myers, Richard M.

AU - Beecham, Gary W.

AU - Reitz, Christiane

AU - Rizzardi, Lindsay F.

AU - Fernandez, Maria Victoria

AU - Goate, Alison M.

AU - Cruchaga, Carlos

AU - Renton, Alan E.

AU - Lopera, Francisco

AU - Kosik, Kenneth S.

PY - 2023/9

Y1 - 2023/9

N2 - INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10−7 or p<1×10−5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

AB - INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10−7 or p<1×10−5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

KW - AAO

KW - ACE

KW - AOO

KW - Alzheimer

KW - CLU

KW - E280A

KW - HS3ST1

KW - HSPG2

KW - LRP1B

KW - PSEN1

KW - SIAH3

KW - TSPAN10

KW - TSPAN14

KW - ZC3H13

KW - age of onset

KW - amyloid

KW - clusterin

KW - heparin sulfate

KW - tetraspanin

UR - http://www.scopus.com/inward/record.url?scp=85150991504&partnerID=8YFLogxK

U2 - 10.1002/alz.13021

DO - 10.1002/alz.13021

M3 - Article

C2 - 36951251

AN - SCOPUS:85150991504

SN - 1552-5260

VL - 19

SP - 3835

EP - 3847

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 9

ER -

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred

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Keywords

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