Imaging QTL studies may have several potential advantages ov

Imaging QTL studies may have several potential advantages over case-control studies, including increased power . Imaging endophenotypes of disease in QTL studies can separate patients and normal subjects more accurately and therefore limit the confound of including asymptomatic subjects in the control group, which is particularly important for the long clinically silent prodromal phase of AD , , , , , , , . These previous imaging QTL studies on AD risk variants and MRI measures used a cross-sectional design and focused on volume of Clotrimazole receptor structures and cortical thickness. We use a longitudinal model to study the genetics of shape asymmetry, yielding increased power for detecting genetic associations , although this may also depend on the genetic architecture of the specific traits being studied. The current study uses longitudinal imaging data from more than 6000 MRI scans and genetic data from 1241 individuals in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We focus on four brain structures (the hippocampus, amygdala, putamen, and caudate) that were selected a priori based on previous reports of increased volume and shape asymmetries in AD , . Shape asymmetry is computed with the Mahalanobis distance of lateralized brain structures within a subject. We include 31 SNPs, selected a priori based on previous GWASs results. These SNPs are primarily composed of 21 candidate SNPs that have been associated with late-onset AD in GWASs , , . If these genetic risk variants for AD also influence shape asymmetry in AD, the results could suggest mechanisms or pathways through which these genes might be exerting their influence in AD. In a more exploratory analysis, 10 additional SNPs are included that have recently been associated to subcortical volume in a large-scale GWAS , but not to AD per se. The motivation is to identify possible genetic predispositions that render the brain vulnerable to shape asymmetry in disease. For example, genes that are associated with smaller hippocampi might render the hippocampus more vulnerable to AD pathology even if the genes are not directly implicated in AD pathology. Methods and Materials
Results In the following, we describe the results of the SNP–asymmetry analyses, where we used models with and without the interaction of SNP and diagnosis together with a quantitative and categorical coding of the diagnosis. Table 1 summarizes all the SNPs that showed significant associations in the different models together with their closest genes, location, major/minor alleles, minor allele frequency, genotype count, population-attributable fractions, or preventive fractions. Significant interactions are reported in more detail, grouped by whether they were identified with a quantitative coding of disease (0 = control [CN]), 1 = MCI stable, 2 = MCI progressor, 3 = AD) (Table 2) or categorical coding (Table 3). We show standardized regression coefficients and p values for the main effects and, in addition, adjusted p values after FDR correction for the interaction. Results are only included in Tables 2 and 3 when the adjusted p value of the interaction is < .05. Interactions with a quantitative coding of disease reveal genetic variants that are associated with shape asymmetry in a stage-dependent manner. Significant associations exist between amygdala asymmetry and rs117253277, as well as between putamen asymmetry and rs683250 and rs6733839 (Table 2). The main SNP effect is not significant for any of these associations after FDR correction. The main diagnosis effect is highly significant for rs117253277 and rs6733839, but not for rs683250. Notably, all regression coefficients for diagnosis are positive, which indicates an increase in asymmetry with the progression of dementia, consistent with our previous results (8). rs117253277 shows a negative coefficient for SNP (−0.539), which means that the presence of a minor allele A decreases the asymmetry. Importantly, the positive interaction (coefficient estimate = 0.585) signifies that asymmetry increases with the number of minor alleles for demented subjects. For rs683250, the pattern is inverted, with minor alleles yielding an increase in asymmetry in controls but a decrease in the demented population. The SNPs (rs117253277 and rs683250) were identified in the subcortical GWASs for amygdala and putamen, respectively, which is consistent with the structures in which we observe disease-dependent associations with asymmetry; rs6733839 was identified in the AD GWASs.