The identification of high-penetrant loss-of-function mutations in abca7 in Alzheimer’s disease

ABCA7 was identified as a risk gene for Alzheimer's disease (AD) in genome-wide association studies (GWAS) and is one of the strongest genes associated with AD risk in the Belgian cohort (OR 1.37 [95%CI 1.09-1.72], corrected p-value 0.007). We performed massive parallel re-sequencing of the full ABCA7 locus, including exons, introns and regulatory regions, in 1529 Belgian AD patients and control individuals, aiming at the detection the underlying genetic variants involved in AD pathogenesis. Conditional logistic regression analysis identified an intronic, low frequency variant, rs78117248 (MAF in AD 3.8%; MAF in control individuals 1.8%), which explained the association signals of the GWAS top SNPs rs3764650, rs4147929 and rs3752246 in the Belgian study population. In addition, we identified an increased frequency of rare variants in patients compared to control individuals, which was mainly driven by an increased proportion of predicted loss-of-function mutations (p-value 0.0002). We identified 4 frameshift mutations (p.E709fs, p.V541fs, p.Q1401fs, p.A2045fs) and 2 nonsense mutations (p.W1214*, p.R1564*). Noteworthy, one frameshift mutation (p.E709fs), resulting from a 7 base-pair deletion, showed a strong founder effect in the Belgian study population. Moreover, this mutation segregated with disease in a family with an autosomal dominant pattern of inheritance of AD. Expression studies in mutation carriers demonstrated a decreased expression of ABCA7 in brain as well as in lymphoblast cell lines. In this base-by-base resequencing of the full ABCA7 locus in a Belgian AD cohort, we found evidence of both intermediate and high penetrant genetic variants in ABCA7, proposing that ABCA7 is not only a risk gene for AD, but also a causal gene, which should be taken into account in genetic diagnostics. Our results suggest haploinsufficiency as the mode of action of pathogenic ABCA7 mutations.