Secuenciación del genoma para estudiar la enfermedad de Alzheimer en población argentina

Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer’s disease

Abstract

Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer’s disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, and has an estimated genetic component of 60–80%1. Over the last decade, more than 20 loci containing common genetic variants (minor allele frequency (MAF) < 5%) have been associated with AD2. The advent of new genetic sequencing technologies has enabled the identification of several rare variants (MAF) < 1%) with moderate effects on AD susceptibility³. In 2017, the International Genomics of Alzheimer’s Project (IGAP) reported four rare coding variants significantly associated with AD4, all of them being involved in microglial-mediated innate immunity. Two of them are novel nonsynonymous variants: a protective one in PLCG2 (rs72824905) and a risk one in ABI3 (rs616338). The other two were previously reported in the susceptibility gene TREM2 (rs143332484 and rs75932628), and are responsible for p.R62H and p.R47H substitutions, respectively. The findings in TREM2 have been consistently replicated in Caucasian4,5,6 and African-American populations7. However, the association of TREM2 p.R47H with AD could not be found in East Asian population, because its frequency is extremely low8,9. This latter observation suggests ethnic variability fostering investigation of these variants in different ethnic groups. Given the increasing population diversity observed in countries all over the world, understanding population-shared and -specific risk factors of AD will translate into improved and specific prevention and/or treatment for people.

Latin America is a vast territory, with a wide diverse admixture of European, Native American, and African ancestral populations. The genetic architecture of sporadic AD has not been studied in this population beyond APOE-ε4. In this report, we provide the first evidence for an association between TREM2, PLCG2, and ABI3 rare variants and AD in the Argentinian population.