Job-related exhaustion risk variant in UST is associated with dementia and DNA methylation

Abstract

Previous genome-wide association and replication study for job-related exhaustion indicated a risk variant, rs13219957 in the UST gene. Epidemiological studies suggest connection of stress-related conditions and dementia risk. Therefore, we first studied association of rs13219957 and register-based incident dementia using survival models in the Finnish National FINRISK study surveys (N = 26,693). The AA genotype of rs13219957 was significantly associated with 40% increased risk of all-cause dementia. Then we analysed the UST locus association with brain pathology in the Vantaa 85+ cohort and found association with tau pathology (Braak stage) but not with amyloid pathology. Finally, in the functional analyses, rs13219957 showed a highly significant association with two DNA methylation sites of UST, and UST expression. Thus, the results suggest a common risk variant for a stress-related condition and dementia. Mechanisms to mediate the connection may include differential DNA methylation and transcriptional regulation of UST.

Figure 1

Cumulative incidence of all-cause dementia (A), Alzheimer’s disease (B), competing event, death without dementia (C), and mortality (D) by rs13219957 genotypes in the FINRISK Study surveys.

Figure 2

Genetic map for the UST gene region and rs13219957 haploblock. The haplotype block around rs13219957 is located at bp 148,936,606–148,953,102 (hg38) in the intron of UST. The haploblock SNPs in LD (r² > 0.2) with rs13219957 and significant association with all-cause dementia in the FINRISK Study surveys and with BRAAK stage in the Vantaa 85+ are coloured yellow. The risk alleles of the SNPs are marked with blue circles. The two DNA methylation sites showing significant associations with the marked SNPs are shown in the top of the figure. Other SNPs of the haplotype block: 1 = rs10457837, 2 = rs1017851, 3 = rs17080218, 4 = 979,429, 5 = rs62426127, 6 = 62,426,128, 7 = rs9399677, 8 = rs6917705, 9 = rs9377180, 10 = rs3734375, 11 = rs9322160, 12 = rs449392, 13 = rs6941568, 14 = rs17080323, 15 = rs2449393, 16 = rs9373582, 17 = rs9390641, 18 = rs12193341, 19 = rs9390643, 20 = rs4895776, 21 = rs7747823, 22 = rs6570914, 23 = rs62426129, 24 = rs62426130, 25 = rs78603586, 26 = rs17728703, 27 = rs10872625, 28 = rs149809941, 29 = rs170080433, 30 = rs74860997, 31 = rs1156561 32 = rs2500511, 33 = rs12211515, 34 = rs2170534, 35 = rs12528390, 36 = rs2500512.