Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2

Abstract

Hippocampal sclerosis of aging (HS-Aging) is a common neurodegenerative condition associated with dementia. To learn more about genetic risk of HS-Aging pathology, we tested gene-based associations of the GRN, TMEM106B, ABCC9, and KCNMB2 genes, which were reported to be associated with HS-Aging pathology in previous studies. Genetic data were obtained from the Alzheimer's Disease Genetics Consortium, linked to autopsy-derived neuropathological outcomes from the National Alzheimer's Coordinating Center. Of the 3251 subjects included in the study, 271 (8.3%) were identified as an HS-Aging case. The significant gene-based association between the ABCC9 gene and HS-Aging appeared to be driven by a region in which a significant haplotype-based association was found. We tested this haplotype as an expression quantitative trait locus using 2 different public-access brain gene expression databases. The HS-Aging pathology protective ABCC9 haplotype was associated with decreased ABCC9 expression, indicating a possible toxic gain of function.

Keywords: CARTS; GWAS; KATP; PGRN; rs704180.

Figure 1

Flow diagram of the subjects included in the analyses. Genetic data were obtained from subjects in ADGC who had the NACC individual IDs. Phenotype data were available from the neuropathological dataset in NACC. The inclusion/exclusion criteria, quality control and removal of ethnic outliers were applied in order. Key: ADGC, Alzheimer’s Disease Genetics Consortium; NACC, National Alzheimer’s Coordinating Center; NP, neuropathological dataset; HS-Aging, hippocampal sclerosis of aging

Figure 2

Proportion and 95% confidence interval of hippocampal sclerosis of aging cases.

Figure 3

Estimation of haplotype frequencies and association using four tag single nucleotide polymorphisms on the ABCC9 gene when assuming a recessive mode of inheritance. Box indicates an exon.