Genetic, psychosocial and clinical factors associated with hippocampal volume in the general population

Abstract

The hippocampus--crucial for memory formation, recall and mood regulation--is involved in the pathophysiology of dementia and depressive disorders. Recent genome-wide association studies (GWAS) have identified five genetic loci associated with hippocampal volume (HV). Previous studies have described psychosocial and clinical factors (for example, smoking, type 2 diabetes and hypertension) to have an impact on HV. However, the interplay between genetic, psychosocial and clinical factors on the HV remains unclear. Still, it is likely that genetic variants and clinical or psychosocial factors jointly act in modifying HV; it might be possible they even interact. Knowledge of these factors might help to quantify ones individual risk of or rather resilience against HV loss. We investigated subjects (N=2463; 55.7% women; mean age 53 years) from the Study of Health in Pomerania (SHIP-2; SHIP-TREND-0) who underwent whole-body magnetic resonance imaging (MRI) and genotyping. HVs were estimated with FreeSurfer. For optimal nonlinear model fitting, we used regression analyses with restricted cubic splines. Genetic variants and associated psychosocial or clinical factors were jointly assessed for potential two-way interactions. We observed associations between HV and gender (P<0.0001), age (P<0.0001), body height (P<0.0001), education (P=0.0053), smoking (P=0.0058), diastolic blood pressure (P=0.0211), rs7294919 (P=0.0065), rs17178006 (P=0.0002), rs6581612 (P=0.0036), rs6741949 (P=0.0112) and rs7852872 (P=0.0451). In addition, we found three significant interactions: between rs7294919 and smoking (P=0.0473), rs7294919 and diastolic blood pressure (P=0.0447) and between rs7852872 and rs6581612 (P=0.0114). We suggest that these factors might have a role in the individual susceptibility to hippocampus-associated disorders.

Figure 1

Flow chart: inclusion and exclusion criteria for participants from the Study of Health in Pomerania (SHIP-2 and SHIP-TREND-0).

Figure 2

(a) The interaction between rs7294919 and smoking status for the mean hippocampal volume (mm³) is depicted. In this plot, an interaction becomes evident between carriers of the CC/CT genotype of rs7294919 and non-smoker for a larger hippocampal volume (P=0.0473). Number of subjects for each combination of genotype and smoking status are given below: rs7294919CT/CC and non-smoker N=140; rs7294919TT and non-smoker N=537; rs7294919CT/CC and smoker N=204; rs7294919TT and smoker N=760. (b) The interaction between rs7294919 and diastolic blood pressure for the mean hippocampal volume (mm³) is depicted. In this plot, an interaction becomes evident between carriers of the CC/CT genotype of rs7294919 and lower diastolic blood pressure for a larger hippocampal volume (P=0.0447). (c) Gene–gene interaction between rs7852872 (ASTN2) and rs6581612 (WIF1) is depicted for the mean hippocampal volume in mm³. This plot shows a considerable interaction for a larger hippocampal volume in CG-genotype carriers of rs7852872 and the CC-genotype carriers of rs6581612 (P=0.0114). Number of subjects for each combination of genotype are given below: rs6581612AA and rs7852872CC: N=350; rs6581612AA and rs7852872GG: N=141; rs6581612AA and rs7852872CG: N=417; rs6581612AC and rs7852872CC: N=242; rs6581612AC and rs7852872GG: N=290; rs6581612AC and rs7852872CG: N=81; rs6581612CC and rs7852872CC: N=44; rs6581612CC and rs7852872GG:N=20; rs6581612CC and rs7852872CG; N=56.