Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment

Abstract

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

Figure 1

Validation of whole-exome sequencing (WES)-identified variant (rs9610775) in larger sample of 315 Alzheimer’s Disease Neuroimaging Initiative Phase 1 (ADNI-1) subjects by surface-based analysis of cortical thickness (a) and voxel-based morphometry (VBM) analysis (b) of gray-matter density at baseline. Statistical maps of SurfStat were thresholded using random field theory (RFT) correction with a corrected significance level of 0.05. The VBM results were presented at P<0.05 (uncorrected). Left hemisphere is shown on the left.

Figure 2

Validation of whole-exome sequencing (WES)-identified variant (rs9610775) using surface-based analysis (a) and voxel-based morphometry (VBM) analysis (b). We showed the dominant effect of rs9610775 on rate of cortical thickness loss (a) and gray-matter density loss (b) over 2 years. Statistical maps of SurfStat were thresholded using random field theory (RFT) correction with a corrected significance level of 0.05. The VBM results are presented at P<0.05 (uncorrected). Left hemisphere is shown on the left.

Figure 3

Validation of whole-exome sequencing (WES)-identified variant (rs1136410) using surface-based analysis (a) of cortical thickness and voxel-based morphometry (VBM) analysis (b) of gray-matter density at baseline. Statistical maps of SurfStat were thresholded using random field theory (RFT) correction with a corrected significance level of 0.05. The VBM results are presented at P<0.05 (uncorrected). Left hemisphere is shown on the left.