ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology

Abstract

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer’s Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer’s Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer’s Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1–3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4–5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10−9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.

Reassessment of Risk Genotypes (GRN,TMEM106B, andABCC9Variants) Associated With Hippocampal Sclerosis of Aging Pathology

“…More detailed information about HS-Aging pathology cases and controls in the NACC dataset without genomics data have been reported (12). Because of the more permissive inclusion criteria and the lack of GWAS-related screening exclusions, the number of subjects in the current study is larger than in the prior GWAS (21). From among the 268 pathologically verified HS-Aging cases and 2957 controls with genotype data now available for analyses, there were 51 HS-Aging cases and 561 controls that were not available for analyses in the previous GWAS study (21); these cases were not from the UK-ADC cohort.…”

“…NACC and ADGC data also included 31 HS-Aging cases and 239 controls from the UK-ADC. DNA samples from these individuals were analyzed in the prior study using PCR-based SNP characterization (21). PCR data from UK-ADC cases agreed with the ADGC SNP data (not shown); therefore ADGC-derived SNP data were used for UK-ADC data in the analyses where all the data were pooled.…”

“…Only individuals who died after age 60 were included in this study. HS-Aging case/control operationalization in NACC were described previously (12, 21); details of the NACC parameter definitions are presented in the Supplemental Material. Relatively few persons with FTLD-TDP, FTLD-tau, other FTLD subtypes, or spongiform encephalopathy were genotyped in our available database (Supplemental Material).…”

“…After exclusions, data from a total of 2343 NACC/ADGC research subjects with genotype and autopsy information outside of UK-ADC data were available for analyses at the time of our prior published HS-Aging GWAS (21). Some cases are included in the current study and not the HS-GWAS project because they met inclusion criteria as stated; however, these research subjects are not an independent cohort for the purpose of a replication experiment.…”

“…A prior genome wide association study (GWAS) that focused on HS-Aging pathology as an endophenotype reported that 2 SNPs in near-perfect linkage disequilibrium with each other (rs704178 and rs704180) in ABCC9 are associated with HS-Aging pathology, with OR = 2.1 and an overall p value = 1.4 × 10 −9 when all the cohorts’ data were combined (21). For practical reasons, we will refer only to rs704180 hereafter.…”