br Discussion In a series of linear

Discussion In a series of linear mixed effects models of longitudinal neuroanatomical change, we have identified genetic risk variants associated with an increase in s7694 shape asymmetry in AD. The closest genes associated with significant SNPs include BIN1 (rs6733839), CD2AP (rs10948363), and ABCA7 (rs4147929), which code for proteins involved in amyloid generation, secretion, and clearance and are thus likely directly implicated in the accumulation of AD pathology. Another gene, ZCWPW1 (rs1476679), has previously been identified to have a preventative effect in AD. Interestingly, we also identified SNPs in the genes TNKS and DLG2 as risk variants for AD-related increases in shape asymmetry. These are SNPs that have previously been associated with subcortical volumes of the amygdala and putamen, respectively (27), and we show that these same SNPs also convey risk for AD pathology in these same structures. Previous reports have found several associations between neuroimaging measures and APOE4(19). In contrast, we found no significant associations between neuroanatomical asymmetry and APOE4, suggesting that the association between APOE4 and atrophy is global, i.e., not symmetric. We review the specifics of each significant SNP below before discussing our results more generally. The interaction of rs117253277 (TNKS) with diagnosis showed the most significant association in our study (p = 6 × 10−6). The SNP was identified in the subcortical GWAS as a common variant associated with differences in amygdala volume. Our results show that the SNP also influences amygdala asymmetry in the context of AD pathology, which provides novel evidence that inherent differences in amygdala volumes make the brain more vulnerable to AD-related patterns of atrophy (i.e., increases in shape asymmetry). Importantly, the interaction between SNP and disease was significant when coding disease both categorically and continuously, which shows that the SNP promotes increases in shape asymmetry already in the preclinical stages of AD in a dose-dependent response. Additional experiments were performed on matched samples to confirm the reliable estimate despite the low minor allele frequency of the SNP. The closest gene is TNKS, which catalyzes the adenosine diphosphate ribosylation of target proteins. rs683250 is an intronic locus within DLG2 and was identified in the subcortical GWAS. It seems to predispose the brain to undergo asymmetric shape atrophy in the progression to AD. For rs683250, however, we also identified a significant main effect of SNP on shape asymmetry, suggesting that the related gene has an effect on putamen asymmetry per se that is magnified in disease. Moreover, we found in the post hoc analysis that there was a significant interaction between SNP and years-from-baseline, indicating that the SNP affects change in putamen asymmetry over time. Genetic variants in DLG2 affect learning and cognitive flexibility (44) and are associated with schizophrenia (45). The link to schizophrenia of the SNP is interesting, because abnormal asymmetries in subcortical structures have previously been reported for schizophrenia 46, 47. rs6733839 is within the BIN1 gene and the most important genetic susceptibility locus after APOE4 for individuals of European ancestry (48). As rs117253277, the SNP was significant for categorical and continuous coding. GWAS studies with MRI measures found association of BIN1 with atrophy in the hippocampus (16), entorhinal and temporal pole cortex (15), and left parahippocampal and right inferior parietal cortex (19). Functions of the BIN1 gene include the production and clearance of amyloid-β and cellular signaling; it increases the risk for AD by modulating tau pathology and is also involved in endocytosis, inflammation, calcium homeostasis, and apoptosis (49). Unlike the two AD-related SNPs related to hippocampus asymmetry, reviewed below, the SNP × disease interaction for rs6733839 was significant for the continuous coding of disease groups, suggesting a linear increase in shape asymmetry with disease progression that includes preclinical stages.