ABCA7 mutations are major contributors to Alzheimer’s disease in Belgian patients

Abstract

AbstractBackground ABCA7 was initially associated with Alzheimer’s disease (AD) in genome‐wide association studies. Recent genetic studies suggest a role for rare premature termination codon (PTC) mutations in ABCA7. While we observed loss of ABCA7 protein for PTC mutations, there was a high variability between mutations due to transcript rescue. Apart from PTC mutations there are missense mutations with unknown effect on ABCA7 protein. Segregation patterns and pathogenicity of ABCA7 mutations are still poorly understood. We aimed at investigating the genetic contribution of ABCA7 in Belgian AD and control cohorts.MethodTargeted resequencing of ABCA7 coding region or whole exome sequencing were used in Belgian AD patient (n = 1478) and control (n = 757) cohorts. Genetic variants were validated by Sanger sequencing. Haplotype analysis was done using STRs flanking ABCA7. Clinicopathological characteristics of carriers were retrospectively reviewed. Mean onset age was 69.3 ± 7.3 years for AD patients and 73.9 ± 8.0 years for controls.ResultIn 69 patient carriers we identified 15 different ABCA7 PTC mutations (69/1478, 4.67%) and 15 PTC in controls (OR = 2.46 (95% CI [1.40–4.33], p = 0.001). The AD PTC carriers had a mean onset age of 69.5 ± 9.7 years (range 48‐90). Also 114 missense mutations were observed in patients (114/1478, 7.71%) and 35 in controls (OR = 1.72 (95% CI [1.17‐2.55], p = 0.006)). The p.G1820S mutation was carried by a familial AD patient aged 65 years and was absent in controls. Genetic screening of family members showed an autosomal dominant inheritance pattern with co‐segregation of p.G1820S on a shared haplotype of at least 2.63 Mb. p.G1820S is located in the second nucleotide binding domain of ABCA7. Whole exome sequencing of family members excluded co‐segregation of variants in other genes associated with AD.ConclusionMutations in ABCA7 are relatively frequent in the Belgian population and particularly in familial AD. Continued identification and characterization of ABCA7 mutations is needed in case clinical genetic testing of ABCA7 is considered. ABCA7 patients might represent an important subtype of AD and new knowledge about their clinical and genetic profile might contribute to diagnosis, risk prediction and development of targeted therapeutics.