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

MORELLI, L; JESSEN, F; KOCHEN, S; CASTAÑO, EM; GRAFF, C; ALVAREZ, V; BULLIDO, M; PILOTTO, A; NACMIAS, B; SPALLETTA, S; SEVILLANO, S; SOLIS, P; SAMPAÑO, M; AZURMENDI, P; SANCHEZ AVALOS, MS; HOFFMANN, P; MILZ, E; OLIVAR, N; LAMBERT, J-C; MAIER, W; POLITIS, DG; BELLENGUEZ, C; SANCHEZ-GARCIA, F; RAMIREZ, A; SANCHEZ-JUAN, P; MANGONE, CA; PANZA, F; SCARO, H; MECOCCI, P; KAIRIYAMA, C; MANCUSO, M; INGELSSON, M; BOSSÙ , P; COTO, E; LISSO, J; CLARIMON, J; JEMAR, G; CAFFARRA, P; LIBERCZUK, C; SORBI, S; CARULLA, ME; GALIMBERTI, D; GALEANO, P; BOSCO, P; HEILMANN-HEIMBACH, S; MEDEL, N; FIERENS, M; HANSES, C; FEZZA, C; BRUSCO, LI; MARTINEZ, LE; PRESTIA, FA; BECKER, J; MUCHNIK, C; DALMASSO, MC

Chicago

Conferencia; AAIC 2018; 2018

Alzheimer's Association

 BACKGROUND: Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with thesusceptibility to Alzheimer?s disease (AD) in Caucasians. Interestingly, althoughTREM2 p.R47H (rs75932628) increasesAD risk in Caucasians and African Americans, its association with AD could notbe observed in East Asian population, because its frequency is extremely low. Hence,frequencies and effects of some genetic variants associated with AD may varyacross 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 populationsample from Argentina and Chile. The admixed nature of this population would helpus 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 Chileancontrols. In addition, Argentinian samples underwent Genome Wide AssociationStudy (GWAS), genotyping 696,375 variant. First, ancestry of rare variantcarriers will be determined. Then, all variants neighboring the rare variants willbe extracted and analyzed in order to evaluate the existence of a commonhaplotype with a suggestive founder effect. These haplotypes will be comparedwith results obtained by the European Alzheimer´s Disease DNA bank, and data in1000 Genomes.  RESULTS: TREM2rs75932628 and ABI3 rs616338 werevalidated 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 showeda suggestive protective effect(OR=0.61 [p=0.39]).CONCLUSIONS: Rarecoding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from South America, and they might originate fromEurope. GWAS results analysis would shed light on this regard.