The first genome-wide association study in the Argentinian and Chilean populations identifies shared genetics with Europeans in Alzheimer's disease

DALMASSO, MARIA CAROLINA; DE ROJAS, ITZIAR; OLIVAR, NATIVIDAD; MUCHNIK, CAROLINA; ANGEL, BÁRBARA; GLOGER, SERGIO; SANCHEZ ABALOS, MARIANA SOLEDAD; CHACÓN, MARÍA VICTORIA; ARÁNGUIZ, RAFAEL; ORELLANA, PAULINA; CUESTA, CAROLINA; GALEANO, PABLO; CAMPANELLI, LORENZO; NOVACK, GISELA VANINA; MARTINEZ, LUIS EDUARDO; MEDEL, NANCY; LISSO, JULIETA; SEVILLANO, ZULMA; IRURETA, NICOLÁS; CASTAÑO, EDUARDO MIGUEL; MONTRREAL, LAURA; THOENES, MICHAELA; HANSES, CLAUDIA; HEILMANN-HEIMBACH, STEFANIE; KAIRIYAMA, CLAUDIA; MINTZ, INÉS; VILLELLA, IVANA; RUEDA, FABIANA; ROMERO, AMANDA; WUKITSEVITS, NANCY; QUIROGA, IVANA; GONA, CRISTIAN; LAMBERT, JEAN-CHARLES; SOLIS, PATRICIA; POLITIS, DANIEL GUSTAVO; MANGONE, CARLOS ALBERTO; GONZALEZ-BILLAULT, CHRISTIAN; BOADA, MERCÈ; TÀRRAGA, LLUÍS; SLACHEVSKY, ANDREA; ALBALA, CECILIA; FUENTES, PATRICIO; KOCHEN, SILVIA; BRUSCO, LUIS IGNACIO; RUIZ, AGUSTÍN; MORELLI, LAURA; RAMÍREZ, ALFREDO

ALZHEIMERS & DEMENTIA

ELSEVIER SCIENCE INC

Año: 2023

1552-5260

INTRODUCTION: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS: We performed GWAS on sporadic Alzheimer´s disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. RESULTS: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio = 2.93 [2.37–3.63], P = 2.6 × 10−23). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. DISCUSSION: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. Highlights: This is the first genome-wide association study on Alzheimer´s disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.