ABCC9: Novel human brain transcripts and an eQTL relevant to hippocampal sclerosis of aging

Abstract

ABCC9 genetic polymorphisms are associated with increased risk for various human diseases including hippocampal sclerosis of aging (HSAging). HS-Aging is a common, high-morbidity brain disease among the elderly that is defined by the presence of the following pathologic features: cell loss and gliosis in the hippocampus, out of proportion to Alzheimertype plaques/tangles, and commonly showing TDP-43 pathology. The two main goals of this study were 1> to describe ABCC9 transcript and 3' untranslated region (3'UTR) variants in human brain, and 2> to determine whether a polymorphism (rs704180) associated with risk for HS-Aging pathology is also associated with variation in human brain ABCC9 transcript expression and/or splicing. Analyses of human brain-derived cDNA revealed splice variants that were not annotated previously. Rapid amplification of ABCC9 cDNA ends (3' RACE) provided evidence of novel 3'UTR portions in human brain. In silico and experimental studies were performed focusing on the single nucleotide polymorphism, rs704180. Analyses from multiple databases, focusing on rs704180 only, indicated that this risk allele is a local expression quantitative trail locus (eQTL). Experimental analyses of RNA, isolated from brain samples of the University of Kentucky Alzheimer's Disease Center biobank, showed increase in ABCC9 transcripts detected among cases with the risk genotype (p<0.05), corresponding with enrichment for a shorter 3' UTR that may be associated with more stable ABCC9 transcript. Thus we report evidence of complex ABCC9 genetic regulation in brain, which may be of direct relevance to human disease.