Common variants at 12q14 and 12q24 are associated with hippocampal volume

Abstract

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

Figure 1. Genome-wide Manhattan plot for hippocampal volume

The plot shows the individual p-values (based on discovery meta-analysis) against their genomic position for hippocampal volume. Within each chromosome, shown on the x-axis, the results are plotted left to right from the p-terminal end. The dashed line indicates the threshold for follow-up, p<4 ×10^-7 and the solid line indicates the threshold for genome-wide significance, p<5×10^-8. The nearest genes are indicated above points that surpassed our significance threshold for follow-up.

Figure 2. Regional plots for hippocampal volume SNPs

Plots are centered on the most significant SNP at a given locus along with the meta-analysis results for SNPs in a region surrounding it (typically ± 100kb). All SNPs are plotted with their discovery meta-analysis p-values against their genomic position, with the most significant SNP in the region indicated as a diamond and other SNPs shaded according to their pairwise correlation (r²) with the signal SNP. The light blue line represents the estimated recombination rates. Gene annotations are shown as dark green lines.

Figure 3. Forest plots for hippocampal volume SNP associations

Plots show the study-specific association estimates (β) and 95% confidence intervals for the discovery and replication stage studies, presented as rectangles and bars. Arrowheads indicate confidence intervals that span beyond the x-axis. Study specific results are indicated by: AGES, Aging Gene-Environment Susceptibility—Reykjavik Study; ARIC, Atherosclerosis Risk in Communities Study, ASPS, Austrian Stroke Prevention Study; ERF, Erasmus Ruchphen Family study; FHS, Framingham Heart Study; RUSH, Religious Order Study & Rush Memory and Aging Project; RS I, RS II, RS III, RS R, independent phases of the Rotterdam Study; TASCOG, Tasmanian Study of Cognition and Gait; 3C, Three City Study. Estimates from the replication phase (3C, RS R) are indicated by open rectangles. The scale is mm³. The association estimate and confidence interval for the meta-analysis combining discovery and second stage results is presented as a diamond. Blank spaces indicate occasions in which a particular study was not able to provide results for a given SNP.