TY - JOUR
T1 - Comparing Alzheimer's genes in African, European, and Amerindian induced pluripotent stem cell–derived microglia
AU - Moura, Sofia
AU - Nasciben, Luciana Bertholim
AU - Ramirez, Aura M.
AU - Coombs, Lauren
AU - Rivero, Joe
AU - Van Booven, Derek J.
AU - DeRosa, Brooke A.
AU - Hamilton-Nelson, Kara L.
AU - Whitehead, Patrice L.
AU - Adams, Larry D.
AU - Starks, Takiyah D.
AU - Mena, Pedro R.
AU - Illanes-Manrique, Maryenela
AU - Tejada, Sergio
AU - Byrd, Goldie S.
AU - Cornejo-Olivas, Mario R.
AU - Feliciano-Astacio, Briseida E.
AU - Nuytemans, Karen
AU - Wang, Liyong
AU - Pericak-Vance, Margaret A.
AU - Dykxhoorn, Derek M.
AU - Rajabli, Farid
AU - Griswold, Anthony J.
AU - Young, Juan I.
AU - Vance, Jeffery M.
N1 - Publisher Copyright:
© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2025/2
Y1 - 2025/2
N2 - INTRODUCTION: Genome-wide association studies (GWAS) studies in Alzheimer's disease (AD) demonstrate ancestry-specific loci. Previous studies in the regulatory architecture have only been conducted in Europeans (EUs), thus studies in additional ancestries are needed. Given the prevalence of AD genes expressed in microglia, we initiated our studies in induced pluripotent stem cell (iPSC) -derived microglia. METHODS: We created iPSC-derived microglia from 13 individuals of either high Amerindian (AI), African (AF), or EU global ancestry, including both AD and controls. RNA-seq, ATAC-seq, and pathway analyses were compared between ancestries in both AD and non-AD genes. RESULTS: Twelve AD genes were differentially expressed genes (DEGs) and/or accessible between ancestries, including ABI3, CTSB, and MS4A6A. A total of 5% of all genes had differential ancestral expression, but differences in accessibility were less than 1%. The DEGs were enriched in known AD pathways. DISCUSSION: This resource will be valuable in evaluating AD in admixed populations and other neurological disorders and understanding the AD risk differences between populations. Highlights: First comparison of the genomics of AI, AF, and EU microglia. Report differences in expression and accessibility of AD genes between ancestries. Ancestral expression differences are greater than differences in accessibility. Good transcriptome correlation was seen between brain and iPSC-derived microglia. Differentially expressed AD genes were in known AD pathways.
AB - INTRODUCTION: Genome-wide association studies (GWAS) studies in Alzheimer's disease (AD) demonstrate ancestry-specific loci. Previous studies in the regulatory architecture have only been conducted in Europeans (EUs), thus studies in additional ancestries are needed. Given the prevalence of AD genes expressed in microglia, we initiated our studies in induced pluripotent stem cell (iPSC) -derived microglia. METHODS: We created iPSC-derived microglia from 13 individuals of either high Amerindian (AI), African (AF), or EU global ancestry, including both AD and controls. RNA-seq, ATAC-seq, and pathway analyses were compared between ancestries in both AD and non-AD genes. RESULTS: Twelve AD genes were differentially expressed genes (DEGs) and/or accessible between ancestries, including ABI3, CTSB, and MS4A6A. A total of 5% of all genes had differential ancestral expression, but differences in accessibility were less than 1%. The DEGs were enriched in known AD pathways. DISCUSSION: This resource will be valuable in evaluating AD in admixed populations and other neurological disorders and understanding the AD risk differences between populations. Highlights: First comparison of the genomics of AI, AF, and EU microglia. Report differences in expression and accessibility of AD genes between ancestries. Ancestral expression differences are greater than differences in accessibility. Good transcriptome correlation was seen between brain and iPSC-derived microglia. Differentially expressed AD genes were in known AD pathways.
KW - ATAC-seq
KW - Alzheimer's disease
KW - RNA-seq
KW - diversity
KW - genetic ancestry
KW - genetic regulatory architecture
KW - iPSC-derived microglia
UR - http://www.scopus.com/inward/record.url?scp=85219505254&partnerID=8YFLogxK
U2 - 10.1002/alz.70031
DO - 10.1002/alz.70031
M3 - Artículo
AN - SCOPUS:85219505254
SN - 1552-5260
VL - 21
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 2
M1 - e70031
ER -
