An intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer ’s disease

AbstractMutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer ’s disease (AD). The influence of other genetic variants inABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions inABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in theABCA7 locus. Expanded VNTR alleles were highly enriched in AD patients [odds ratio  = 4.5 (1.3–24.2)], and VNTR length inversely correlated with amyloid β1 –42 in cerebrospinal fluid andABCA7 expression. In addition, we identified three novelABCA7 alternative splicing events. One isoform in particular —which is formed through exon 19 skipping—lacks the first nucleotide binding domain of ABCA7 and is abundant in brain tissue. We observed a tight correlation between exon 19 skipping and VNTR length. Our findings underline the importance of studying repetitive DNA in complex disorders and expand the contribution of genetic and transcript variation inABCA7 to AD.
Source: Acta Neuropathologica - Category: Neurology Source Type: research