Rare coding variants in PLCG2, ABI3, and TREM2 genes are associated with Alzheimers disease in an Argentinian sample. Is it a European heritage

GALEANO, PABLO; RAMIREZ, ALFREDO; PRESTIA, FEDERICO ARIEL; MORELLI, LAURA; DALMASSO, MARIA CAROLINA; CASTAÑO, EDUARDO MIGUEL

Chicago

Congreso; The Alzheimers Association International Conference (AAIC 2018); 2018

Alzheimers Association

El trabajo incluye, además de los listados, otros 49 co-autores. Por razones prácticas se listan los co-autores de nuestro laboratorio y el último autor y se remite al lector al poster que se adjunta o a la página web del congreso donde se listan todos los co-autores. Background. Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer?s disease (AD) in Caucasians. Interestingly, although TREM2 p.R47H (rs75932628) increases AD risk in Caucasians and African Americans, its association with AD could not be observed in East Asian population, because its frequency is extremely low. Hence, frequencies and effects of some genetic variants associated with AD may vary across ethnicities. Latin American populations are admixture of Native, Caucasian, and African ancestors, which present a huge gap in AD genetic studies. Consequently, we explored the effect of these rare coding variants on AD susceptibility in a population sample from Argentina and Chile. The admixed nature of this population would help us elucidate the ancestry of these rare variants. Methods. Four rare coding variants, in TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) genes, were genotyped in 419 AD cases and 488 healthy controls from Argentina. Statistical power was increased by including in the analysis 266 Chilean controls. In addition, Argentinian samples underwent Genome Wide Association Study (GWAS), genotyping 696,375 variant. First, ancestry of rare variant carriers will be determined. Then, all variants neighboring the rare variants will be extracted and analyzed in order to evaluate the existence of a common haplotype with a suggestive founder effect. These haplotypes will be compared with results obtained by the European Alzheimer´s Disease DNA bank, and data in 1000 Genomes. Results. The four variants were detected in the sample with minor allele frequencies similar to those reported in Caucasians. TREM2 rs75932628 and ABI3 rs616338 were validated as risk factors for AD (OR=7.17, p=0.04 and OR=2.77, p=0.04, respectively) in this Latin American sample. The PLCG2 rs72824905 showed a suggestive protective effect (OR=0.61, p=0.39). Currently we are running the analysis to determine ancestry and the haplotype associated to these rare variants. Conclusions. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from South America, and they might originate from Europe. GWAS results analysis would shed light on this regard.